Weight Control and Slimming Ingredients in Food Technology

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October 15, 2009

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Printer Name: Yet to Come

WEIGHT CONTROL AND SLIMMING INGREDIENTS IN FOOD TECHNOLOGY

Susan S. Cho

A John Wiley & Sons, Inc., Publication

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Susan S. Cho

A John Wiley & Sons, Inc., Publication

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Edition first published 2010 C 2010 Blackwell Publishing Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical, and Medical business to form Wiley-Blackwell. Editorial Office 2121 State Avenue, Ames, Iowa 50014-8300, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book, please see our website at www.wiley.com/wiley-blackwell. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Blackwell Publishing, provided that the base fee is paid directly to the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license by CCC, a separate system of payments has been arranged. The fee codes for users of the Transactional Reporting Service are ISBN-13: 978-0-8138-1323-3/2010. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Library of Congress Cataloging-in-Publication Data Weight control and slimming ingredients in food technology / [edited by] Susan Sungsoo Cho. p. ; cm. Includes bibliographical references and index. ISBN 978-0-8138-1323-3 (hardback : alk. paper) 1. Weight loss preparations. 2. Functional foods. 3. Dietary supplements. I. Cho, Sungsoo. [DNLM: 1. Overweight–prevention & control. 2. Dietary Supplements. 3. Food. 4. Overweight–diet therapy. 5. Weight Loss. WD 210 W4193 2010] RM222.2.W2968 2010 613.2 5–dc22 2009031847 A catalog record for this book is available from the U.S. Library of Congress. R Set in 11/13 pt Times by Aptara Inc., New Delhi, India Printed in Singapore

1 2010

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Contents Contributors

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Preface

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Introduction Part I

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Lipids based ingredients

Chapter 1

Conjugated Linoleic Acid David J. Cai

Chapter 2

Appetite Suppression Effects of PinnoThinTM (Korean Pine Nut Oil) Corey E. Scott

Chapter 3

Sucrose Fatty Acid Ester (Olestra) John C. Peters

Chapter 4

The Effects of a Novel Fat Emulsion r / FabulessTM ) on Energy Intake, Satiety, (Olibra Weight Loss, and Weight Maintenance Rick Hursel and Margriet Westerterp-Plantenga

3

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Part II Protein based ingredients Chapter 5

Chapter 6

The Role of Dairy Products and Dietary Calcium in Weight Management Lisa A. Spence, and Raj G. Narasimmon Gelatin—A Versatile Ingredient for Weight Control Klaus Flechsenhar and Eberhard Dick

67 95

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Chapter 7

Chapter 8

Chapter 9

Contents

α-Lactalbumin in the Regulation of Appetite and Food Intake Arie G. Nieuwenhuizen, Ananda Hochstenbach-Waelen, and Margriet Westerterp-Plantenga The Effects of Casein-, Whey-, and Soy Protein on Satiety, Energy Expenditure, and Body Composition Margriet Veldhorst, Anneke van Vught, and Margriet Westerterp-Plantenga Soy Peptides and Weight Management Cristina Mart´ınez-Villaluenga and Elvira González de Mej´ıa

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Part III Functional components Chapter 10

Chapter 11

Chapter 12

The Effects of Caffeine and Green Tea on Energy Expenditure, Fat Oxidation, Weight Loss, and Weight Maintenance Rick Hursel and Margriet Westerterp-Plantenga Mechanisms of (−)-Epigallocatechin-3-Gallate for Antiobesity Hyun-Seuk Moon, Mohammed Akbar, Cheol-Heui Yun, and Chong-Su Cho Capsaicin Astrid J.P.G. Smeets and Margriet Westerterp-Plantenga

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Part IV Fiber based ingredients Chapter 13

r , Resistant Dextrin, in Satiety Control NUTRIOSE Susan S. Cho and Iris L. Case

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Chapter 14

Fiber and Satiety Susan S. Cho, Iris L. Case, and Stephanie Nishi

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Appendix

Global Suppliers of Ingredients for Weight Control

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Index

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Contributors Mohammed Akbar, PhD (11) Laboratory of Molecular Signaling National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda, MD USA David J. Cai, PhD (1) Cognis Corp. Nutrition and Health LaGrange, IL USA Iris L. Case, BS (13, 14) NutraSource Clarksville, MD USA

Eberhard Dick (6) Food Application, GELITA AG Uferstraße, Eberbach Germany Klaus Flechsenhar, MD (6) Senior Manager Medical Affairs Research and Development GELITA AG Uferstraße, Eberbach Germany Elvira González de Mej´ı a, PhD (9) Department of Food Science and Human Nutrition University of Illinois Urbana, IL USA

Chong-Su Cho, PhD (11) Research Institute for Agriculture and Life Sciences, and School of Ananda Hochstenbach-Waelen, Agricultural Biotechnology PhD student (7) Seoul National University, Seoul Department of Human Biology South Korea Nutrition and Toxicology Research Institute Susan S. Cho, PhD (13, 14) Maastricht (NUTRIM) NutraSource Maastricht University, Maastricht Clarksville, MD The Netherlands USA vii


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Rick Hursel, MSc (4, 10) Dept. of Human Biology Maastricht University 6200 MD Maastricht The Netherlands Cristina Mart´ınez-Villaluenga, PhD (9) Department of Food Science and Human Nutrition University of Illinois Urbana, IL 61801, USA Hyun-Seuk Moon, PhD (11) Laboratory of Molecular Signaling National Institute on Alcohol Abuse and Alcoholism National Institutes of Health Bethesda, MD USA Raj G. Narasimmon, PhD (5) Vice President, Product Research Dairy Management Inc. Rosemont, IL USA Arie G. Nieuwenhuizen, PhD (7) Department of Human Biology Nutrition and Toxicology Research Institute Maastricht (NUTRIM) Maastricht University, Maastricht The Netherlands Stephanie Nishi, BS (14) University of Toronto Toronto, Canada

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John C. Peters, PhD (3) P&G Nutrition Science Institute The Procter & Gamble Company Cincinnati, OH USA Dr. Corey E. Scott, PhD (2) Nutrition Manager Lipid Nutrition, B.V. Astrid J.P.G. Smeets, PhD (12) Maastricht University Medical Center Maastricht The Netherlands Lisa A. Spence, PhD, RD (5) American Dietetic Association Chicago, IL, USA Anneke van Vught, MSc (8) Nutrition and Toxicology Research Institute Maastricht (NUTRIM) Maastricht University Medical Centre Maastricht, The Netherlands. Margriet Veldhorst, MSc (8) Maastricht University Medical Centre Maastricht, The Netherlands.


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Contributors

Prof. Dr. Margriet Westerterp-Plantenga, PhD (4, 7, 8, 10, 12) Department of Human Biology Nutrition and Toxicology Research Institute Maastricht (NUTRIM) Maastricht University, Maastricht The Netherlands

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Cheol-Heui Yun, PhD (11) Research Institute for Agriculture and Life Sciences, and School of Agricultural Biotechnology Seoul National University, Seoul South Korea


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Preface The incidence of obesity is rising at alarming rates throughout the world. In the United States, it has become a public health epidemic. Some estimates indicate that 1.1 billion individuals are overweight worldwide (WHO, 2009). Food manufacturers are responding to this epidemic by developing low-calorie, low-fat foods and incorporating into these foods ingredients that actively promote body weight reduction and control. The identification of ingredients that promote weight management should be actively pursued and done so, based on credible science. Numerous ingredients are available with varying levels of scientific evidence supporting a weight management potential. These ingredients range from wellresearched ones, such as novel fat emulsion, sucrose polyester, alginate, guar gum, resistant starches, green tea polyphenols, protein from dairy sources, and conjugated linolenic acid, to ingredients, such as Hoodia gordonii and capsaicin, that have only limited available data to support their possible role in weight management. In this book, each chapter presents data on efficacy, mechanism of action, and safety of the various ingredients. Current and potential food applications for these ingredients are provided as well. This book offers the most up-to-date information and research findings for each ingredient. Information on the global sources of these new and innovative materials is also included. This book will be useful to those in food manufacturing responsible for product development, as well as to nutritionists and other health professionals who have an interest and responsibilities in the weight management of their clients.

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Introduction Currently, over 60% of the U.S. population are overweight or obese (CDC, 2009). The condition is widespread across all states and demographic groups in the United States. Children are not immune from this disturbing trend. Obesity prevalence among 4-year-old U.S. children (mean age 52.3 months) was 18.4% in 2005 (Anderson and Whitaker, 2009). The prevalence of overweight and obesity has steadily increased among some sex and age groups of preschool children since 1971–1974. More than 10% of 4- and 5-year-old girls were overweight in 1988 through 1994 compared with 5.8% in 1971 through 1974 (Ogden et al., 1997). Other countries, both developed and underdeveloped, are also observing this trend. In the United Kingdom, the percentage of overweight adults is 51%, in Russia 54%, in Germany 50%, in Brazil 36%, and in China 15% (WHO, 2009). Weight gain and obesity are risk factors for type 2 diabetes, gallbladder disease, hypertension, coronary heart disease, osteoarthritis, and certain cancers (Nguyen et al., 2008). Analysis of NHANES 1999–2004 revealed that increasing body mass index is associated with an increase in the prevalence of hypertension (18.1% for normal weight to 52.3% for obesity class 3), diabetes (2.4% for normal weight to 14.2% for obesity class 3), dyslipidemia (8.9% for normal weight to 19.0% for obesity class 3), and metabolic syndrome (13.6% for normal weight to 39.2% for obesity class 3). With normal-weight individuals as a reference, individuals with obesity class 3 had an adjusted odds ratio of 4.8 (95% CI 3.8–5.9) for hypertension, 5.1 (95% CI 3.7–7.0) for diabetes, 2.2 (95% CI 1.7–2.4) for dyslipidemia, and 2.0 (95% CI 1.4–2.8) for metabolic syndrome (Nguyen et al., 2008). These findings have important public health implications for the prevention of obesity. Major causes for increased overweight and obesity prevalence are increased calorie intakes and sedentary lifestyles. In the past two decades, caloric intake has risen significantly and physical activity has dramatically xiii


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declined. Fiber intake is low, but the consumption of energy-dense foods, snacks, and drinks has increased. Researchers reported that energy density of foods was associated with diet quality and body weight (Kant et al., 2008). Food manufacturers are responding to this epidemic by developing the foods which may help consumers better manage their satiety and body weight. The identification of ingredients that promote weight management should be actively pursued. Numerous ingredients have been claimed for their efficacy for satiety and/or weight management. In this book, each chapter offers comprehensive thoughts on various ingredients. This book reviews the most relevant satiety clinical studies on various ingredients including conjugated linoleic acid high-amylose corn starches (HACS), sucrose polyester, novel fat emulsions, and Korean pine nut oil. Although these ingredients have been shown to impact satiety, careful consideration has to be given to the exact clinical protocol, dosing regime, and specific delivery form. Even within each class of macronutrients, variable degrees of efficacy and potency were noted. In addition to macronutrients, this book covers other functional ingredients such as green tea, coffee, and capsaicin. We would like to thank all researchers in nutrition and weight management who made this book possible. Susan Cho

References Anderson SE, Whitaker RC. Prevalence of obesity among US preschool children in different racial and ethnic groups. Arch Pediatr Adolesc Med 2009;163:344–348. CDC. Available online at http://www.cdc.gov/datastatistics. 2009. Kant AK, Andon MB, Angelopoulos TJ, Rippe JM. Association of breakfast energy density with diet quality and body mass index in American adults: National Health and Nutrition Examination Surveys, 1999– 2004. Am J Clin Nutr 2008;88:1396–1404. Nguyen NT, Magno CP, Lane KT, Hinojosa MW, Lane JS. Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: findings from the National Health and Nutrition Examination Survey, 1999 to 2004. J Am Coll Surg 2008;207:928–934.


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Ogden CL, Troiano RP, Briefel RR, Kuczmarski RJ, Flegal KM, Johnson CL. Prevalence of overweight among preschool children in the United States, 1971 through 1994. Pediatrics 1997;99:E1. WHO. Available online at http://www.who.int/en. 2009.


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PART I

Lipid based ingredients

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CHAPTER 1

Conjugated Linoleic Acid David J. Cai, PhD

Abstract As consumers are becoming more educated about the importance of improving body composition not just weight loss, that is, preserving and increasing lean muscle mass while reducing body fat at the same time, public interest for functional ingredients, such as conjugated linoleic acids (CLAs), that can deliver such benefits is also growing. Research findings indicate that CLA may be useful in improving human health in controlling body fat gain and enhancing lean body mass. Functional foods that are developed with such ingredients could encourage healthier consumer attitudes toward body image and weight loss. The chapter reviews current research on mechanism, safety and effectiveness, regulatory details, and product development issues of CLA. These details provide food developers, marketers, academic researchers, and health professionals an overview of CLA and its application in functional foods.

Introduction The current focus of the weight management category has steered away from typical stimulants-based concepts, which have been the basis for the products of the past. New trends include insulin management, appetite control, and optimal body composition (reduce body fat reduction and increase lean muscle mass). Consumers are becoming more educated about overall body composition, not just weight loss; they are learning about the importance of preserving and increasing lean muscle mass while reducing body fat at the same time. Preventing fat regain is another area of focus 3


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Lipid based ingredients OH

H3C

c 9,t 11 O OH

H3C

t10,c12 O

Figure 1.1. Chemical structure of the two primary CLA isomers of Tonalin TG 80 (provided by Cognis GmbH).

especially for yo-yo dieters. Functional foods that are developed to target fat and retain lean body mass could encourage healthier attitudes toward body image and weight loss. A recently published meta-analysis study along with other studies put conjugated linoleic acid (CLA) to the spotlight as the candidate for a healthier weight management aid. In the meta-analysis, the authors concluded that CLA could enhance overall health by effectively reducing body fat, maintaining or increasing lean muscle mass, and potentially preventing weight and fat regain commonly experienced by adults, especially yo-yo dieters (Whigham et al., 2007). Although this effect is modest, it could be important if accumulated over time, especially in an environment where continuous weight gain is the norm in the adult population. The following paragraphs provide an overview of CLA and its application in functional foods.

Background CLA is found primarily in dairy products and ruminant meat as a result of bacterial biohydrogenation of linoleic acid in the rumen. CLA is a collective term for many modified forms of linoleic acid that are resulted from double bonds occurring in different locations along the fat molecules. The cis-9,trans-11-CLA (c9,t11-CLA) and trans-10,cis-12-CLA (t10,c12CLA) are the two most bioactive isomers (see Fig.1.1) (Pariza et al., 2001) whereas the cis-9,trans-11 isomer is also the predominant form in whole fat dairy products and ruminant meat accounting for more than 90% of CLA intake in the diet (Bhattacharya et al., 2006). The estimated human intake of CLA from the U.S. diet is approximately 200 mg/day (Ritzenthaler et al., 2001).


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In addition to the bacterial biodehydrogenation in ruminant animals, CLA can also be produced commercially from safflower oil, such as the r Tonalin CLA manufactured by Cognis GmbH (Monheim, Germany). The high-quality CLA consists of approximately equal amounts of the c9,t11 (40%) and t10,c12 isomers (40%) with less than 2% of other isomers. It is produced by chemical isomerization of safflower linoleic acid under alkaline conditions. CLA appears to have effects on the function of body based on its two most bioactive isomers. The c9,t11- and t10,c12-CLA isomers either act alone or in concert to produce their effects. In vitro and animal studies indicated that the t10,c12 isomer is solely responsible for the reduction of body fat gain while c9,t11-CLA enhances growth and feed efficiency in young rodents (reviewed in Ritzenthaler et al., 2001). In other cases, the isomers act together to induce an effect (Ip et al., 2002). This may be due to the fact that the mixed isomers seem to involve additive biochemical pathways or multiple interactions with numerous metabolic signaling pathways, which results in the superiority of the isomer blend (Ritzenthaler et al., 2001).

Absorption and Metabolism The general metabolic fate of CLA is considered to be similar to that of linoleic acid (Banni, 2002). Like most fatty acids, CLA is well absorbed across the gastrointestinal mucosa. It is also widely distributed throughout the body, metabolized via oxidation and desaturation and extensively excreted from the body in expired air, and lesser amounts in urine and feces (Sébédio et al., 2003). Both isomers may also be oxidized in the β-oxidation pathway.

Mechanism for Decreasing Body Fat Mass The exact mechanism through which CLA is able to decrease body fat mass is yet not clear. However, it does appear that CLA has two main sites of action: the adipocytes that are the principal site of fat storage, and the skeletal muscle cells that are the principal site of fat burning (reviewed in Ritzenthaler et al., 2001 and Pariza et al., 2001). Studies have shown that CLA inhibits the activity of lipoprotein lipase (LPL) and stearoyl-CoA desaturase, and stimulates the breakdown of stored fat in the adipocytes (lipolysis) (Choi et al., 2000; Gavino et al., 2000; Park et al., 1997). LPL is the enzyme that transfers dietary fat after a meal into


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the adipocytes for storage. By inhibiting the LPL activities, CLA could reduce lipid uptake into adipocytes (Park et al., 1997, 1999). The t10,c12CLA isomer may also affect the number of newly formed adipocytes by reducing preadipocyte differentiation (Brown et al., 2003; Kang et al., 2003), or existing number of adipocytes by increasing adipocyte apoptosis or programmed cell death (Evans et al., 2000; Fischer-Posovszky et al., 2007; Hargrave et al., 2002; LaRosa et al., 2006; Tsuboyama-Kasaoka et al., 2000). Other evidence demonstrated that carnitine palmitoyltransferase (CPT) activity is increased with CLA. The increased CPT activity in skeletal muscle cells enhances the rate of fatty acid transport into the mitochondria and results in an increased β-oxidation (Park et al., 1997). This may explain the enhancement of oxygen consumption and energy expenditure reported in CLA-fed OLETF rats (Nagao et al., 2003) and more recent in human studies (Close et al., 2007). In summary, it is likely that CLA decreases body fat mass through four possible actions: 1. Decreasing the amount of fat that is stored after eating (decreases LPL). 2. Increasing the rate of fat breakdown in fat cells (lipolysis) and the rate of fat burning in the mitochondria (CPT and ß-oxidation). 3. Reducing proliferation and differentiation of preadipocytes to mature adipocytes. 4. Decreasing the total number of fat cells (apoptosis). The mechanisms are supported mostly by data from animal studies and in vitro studies using cultured mouse adiposities, human adipocytes, and modified markers of differentiation as well as cultured human preadipocytes (reviewed in Ritzenthaler et al., 2001). CLA may also decrease muscle protein breakdown, reduce the release of proinflammatory cytokines, and improve insulin-stimulated glucose transport (energy supply) into muscle that results in maintained or even increased muscle mass (Henriksen et al., 2003).

Body Fat Reduction by CLA Introduction CLA had been shown to reduce body fat and increase lean body mass in several species of animals, including chicken, mice, rats, and pigs (Ritzenthaler et al., 2001). In addition to extensive animal data, over 30


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clinical studies investigating doses from 0.7 to 6.8 g/day of the 50:50 mixture in over 1,700 human subjects for periods of 12 weeks to 2 years have been published. Many clinical studies have shown that CLA improves body composition with or without combination with exercise and in lean, overweight, and even obese subjects. For example, a long-term study demonstrated a 9% decrease in body fat in overweight subjects following 1-year supplementation with CLA without additional exercise (Gaullier et al., 2004, 2005). A recent study demonstrated its effect in overweight subjects during holiday period (Watras et al., 2006). Another recent study further demonstrated that the body fat reduction mainly occurs in waist and leg area suggesting a body-shaping benefit (Gaullier et al., 2007) and is effective for both men and women subjects. Although a few studies used up to 6.8 g of CLA mixture/day (Kreider et al., 2002; Steck et al., 2007), the most common dosage is about 3.2 g of active CLA-mixed isomers per day either as free fatty acids or as triglycerides. While several studies showed significant reductions in body fat and/or other parameters of body composition, there are others that did not find such benefits. To fully understand why there is inconsistency in CLA study outcomes, it is critical to take into consideration the key factors to the quality and outcome of CLA studies: 1. Quality of testing material 2. Suitable methods for measuring body composition 3. Study design includes random, double-blind design with adequate number of subjects. Other design factors include suitable dosage and study duration.

Quality of Testing Material The quality of material is critical to clinical study outcomes. A CLA material containing high amount of less bioactive CLA isomers would certainly hamper the body fat reduction effect of the c9,t11- and t10,c12-CLA isomers (Gaullier et al., 2002). High-quality CLA-mixed isomers are usually manufactured under patented technology and process. In the case of r Tonalin CLA, manufactured by Cognis GmbH, the raw material used is food grade safflower oil rich in linoleic acid (C18:2 c9,c12) and containing very few other polyunsaturated fatty acids. The high linoleic acid then goes through isomerization to form CLA under a nitrogen atmosphere in order to limit oxidation. By carefully optimizing the reaction conditions, only the


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Lipid based ingredients Tonalin ® CLA

Technical-grade CLA c 9,t 11 CLA c9,t 11 CLA

65

t 10,c12 CLA

t 10,c12 CLA

70

min

65

70

min

Figure 1.2. Comparison of GC–MS profile of unpatented and patented CLA products (provided by Cognis GmbH).

c9,t11- and t10,c12-CLA isomers are formed in a 1:1 ratio. Conventional deodorization and/or bleaching stages in accordance with cGMP are performed to further improve the quality of the final CLA product. The finished product contains >80% of c9,t11- and t10,c12-CLA isomers with 8%, lower than that in the placebo group. This loss of body fat coincided with a slight increase of lean body mass (0.6 kg) and a reduction of body weight (−1.6 kg) whereas subjects receiving the placebo did not show these changes (Gaullier et al., 2004). In the follow-up study, 125 overweight (BMI 25–30) volunteers from both CLA group and the initial placebo group received 3.4 g CLA/day (given as Tonalin 80 TG). Subjects who lost body fat mass in year 1 did not lose further body fat, but were able to prevent fat regain. Subjects from the initial placebo group lost body fat mass significantly in the second year after they were given CLA supplement (Gaullier et al., 2005). The authors concluded that long-term supplementation with CLA reduced body fat mass (BFM) in healthy overweight adults and helped prevent fat regain. A recent long-term study was conducted in 120 subjects who were put on energy restriction diet over a period of 8 weeks and investigated if CLA supplementation (3.4 g/day) for 1 year would prevent body weight and body fat regain. Although the differences on body fat regain did not reach statistical significance, the authors found that CLA group regained less body fat (2.1 kg with CLA vs. 2.7 kg with placebo) and more lean body mass (Larsen et al., 2006). A recent randomized, double-blind CLA study using the fourcompartment model method found that giving 40 healthy, overweight subjects 3.2 g CLA/day or placebo (safflower oil) for 6 months, the CLA supplementation significantly reduced body fat (−1.0 kg; p < 0.05) and weight gain during a period that included the holiday season (November to January). The placebo group, however, gained weight and body fat during the same period (Watras et al., 2006). In a follow-up study, the research group discovered that fat oxidation was increased significantly during sleep (15%) compared to baseline in the CLA group, while it was decreased in the placebo group (−22%) (Close et al., 2007). Furthermore, the total energy expenditure during sleep was also increased in the CLA group. The results may explain partially the body fat reduction effect of CLA in the holiday study. The four-compartment model method is a combination of a few existing accurate methods, thus, making it the most accurate method so far to measure body composition. This method is able to detect even subtle change in body composition.


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In Exercise Subjects with BMI < 25 CLA not only has effect on body fat reduction in overweight or obese subjects, the same effect was demonstrated in lean subjects as well. An earlier study investigated the effect of CLA supplementation (1.8 g/day) upon body fat in healthy, lean humans over 12 weeks (Thom et al., 2001). In this placebo-controlled double-blind study, all 20 subjects (age 18–39 years) performed a standardized physical exercise for 90 minutes, three times per week. While the placebo group experienced no changes in body composition, the CLA-treated group reduced BFM from 22% to 17.5%. The number of subjects, however, was relatively small. Another study evaluated whether CLA supplementation during resistance training affects body composition, strength, and/or general markers of catabolism and immunity (Kreider et al., 2002). In a double-blind and randomized study, 23 experienced, resistance-trained subjects were matched according to body mass and training volume and randomly assigned to supplement their diet with 6 g CLA/day versus placebo for 4 weeks. Although some statistical trends were observed with moderate to large effect sizes, CLA supplementation did not significantly affect (p > 0.05) changes in total body composition parameters, or general markers of catabolism and immunity during training. Unfortunately, the study duration was too short and the number of subjects was too small to observe any significant effects. In a recent longer duration study, 76 subjects were randomized to receive 5 g CLA/day or placebo for 7 weeks while performing resistance training three times per week. The CLA group had greater increases in lean tissue mass and greater losses of fat mass by maintaining the resting metabolic rate (RMR) while RMR decreased in the placebo group. Additionally, supplementation with CLA lessened the catabolic effects of training (measured as myofibrillar protein degradation, 3-MH). This finding suggests that CLA might be most effective if combined with physical exercise (Pinkoski et al., 2006). In Subjects with BMI > 25 Kamphuis et al. (2003aa, 2003bb) tested the hypothesis that CLA might reduce the regain of body fat and body weight in overweight adults who had undergone weight loss. All subjects received a very low calorie diet for 3 weeks followed by a 13-week intervention period during which they ate ad libitum but were given CLA (1.8 or 3.6 g) or placebo each day. The subjects consuming CLA (either dose level) significantly gained



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lean mass, but not fat mass comparing to the controls, and a significantly enhanced RMR. Interestingly, measures of appetite, feelings of fullness and satiety were also increased while feelings of hunger were decreased by CLA ingestion. In another clinical study (Blankson et al., 2000) with overweight and obese subjects, BFM was reduced by 5.7% after 3 months of supplementation with CLA (3.4 g/day). The reduction in BFM was accompanied by a proportional increase in lean body mass and an improved overall feeling of well-being. Higher dosages of CLA were tested, but did not result in greater effects upon body composition. In a recent study, 48 healthy obese subjects of both genders were randomized to receive placebo, 3.2 g CLA/day, or 6.4 g CLA/day for 12 weeks. Subjects were instructed to maintain their current diet and exercise routines throughout the study period. Although no significant difference on body fat was found between two groups, lean body mass was increased significantly by 0.64 kg in the 6.4 g of CLA group/day (p < 0.05) after 12 weeks of intervention (Steck et al., 2007).

Body Shaping and CLA A new study recently demonstrated that CLA may have body-shaping effect by losing fat in certain areas of body. In a randomized, doubleblind, placebo-controlled study (Gaullier et al., 2007), 83 overweight and obese subjects (BMI 28–32 kg/m2 ) took 3.4 g of a 50:50 CLA mixture or placebo (olive oil) per day for 6 months; CLA significantly decreased BFM at month 3 (−0.9%, p < 0.05) and at month 6 (−3.4%, p < 0.05) compared to placebo. The reduction in fat mass was mostly in the legs (−0.8 kg, p < 0.001), and in women (−1.3 kg, p ≤ 0.05) with BMI over 30 (−1.9 kg, p < 0.05), compared to placebo. Waist/hip ratio was also decreased significantly (p < 0.05) compared to placebo. Lean body mass was increased (+0.5 kg, p < 0.05) within the CLA group. All changes were independent of diet and/or physical exercise.

CLA Efficacy in Foods The body fat reduction benefits of CLA began to draw mainstream food manufacturers to launch functional foods in an attempt to solve the widespread obesity problem. Since 2004, there are a few CLA-enriched functional foods that have been launched in Europe. One of the most successful examples is from a Spanish firm Asturiana. Asturiana has launched


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a series of CLA-fortified dairy and fruit products in Spain since 2004 and has accomplished over 47 million Euros annual sales since then. It is important to study the efficacy of CLA in food matrix because of any potential synergy or interaction between CLA and food components. A recent study confirmed that CLA in foods is as effective as it is in supplement forms (Laso et al., 2007). Sixty healthy subjects of both genders (BMI 25–35 kg/m2 ) were randomized to receive a placebo or 500 mL milk supplemented with 3 g CLA for 12 weeks. Total fat mass was decreased significantly among subjects with a BMI ≤ 30 kg/m2 in the CLA-fortified milk group (∼2%, p = 0.01) while no changes were detected in the placebo group. Trunk fat mass showed a trend toward reduction (∼3%, p = 0.05). The authors concluded that supplementation of milk with 3 g CLA over 12 weeks results in a significant reduction of fat mass in overweight but not in obese subjects. In a smaller study, 31 overweight subjects were given CLA-fortified milk (with or without 3 g CLA, respectively) in combination with programmed physical activity (60 minutes each time, four times a week) for a total duration of 4 months (Nazare et al., 2007). The group receiving 3 g CLA/day decreased BMI (p < 0.0001), and subcutaneous fat mass measured by anthropometry (p < 0.002) and the total fat mass measured by air displacement pletismography (Bod Pod) (p < 0.0001) in comparison to the placebo group (the physical activity level was identical). Another recent study using CLA-fortified yogurt, however, failed to find a significant body fat reduction effect in 44 healthy subjects even though the basal energy expenditure increased significantly in the CLA group (+5 kJ/kg fat-free mass/day on day 98 vs. day 0, p = 0.03) suggesting a potential fat burning effect of CLA (Villegas et al., 2007). The subjects were randomly assigned to consume daily either a 50:50 CLA-mixed isomer (3.76 g/day) supplemented yogurt or a placebo yogurt for 98 days. Meta-Analysis and Summary Despite some inconsistent results on body fat reduction, the totality of the evidence suggests a moderate body fat reduction by CLA mixture confirmed by a recent meta-analysis study (Whigham et al., 2007). The meta-analysis study collected and analyzed 18 eligible CLA studies that were longitudinal randomized, double-blind, placebo-controlled human clinical trials using validated body composition measurements. The researchers concluded that among participants given 3.2 g/day, CLA produces a significant but modest reduction of fat mass of 0.2 pounds a week or 0.8 pounds a month compared to participants in the placebo group.


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Although this effect is modest, it could be important if accumulated over time, gradual weight gain is the norm in the adult population. In summary, when the high-quality CLA-mixed isomers were used in proper designed studies with adequate number of subjects, there was an indication of significant BFM reduction relative to placebo controls regardless of delivery vehicle. This effect was observed in both short-term and long-term studies and in various subject populations. More importantly, the fat reduction seems to occur in waist and leg areas where the accumulation of fat is the most detrimental to health. Although further evidence is needed, the potential of this benefit by CLA on long-term health is too important to be ignored. Furthermore, CLA may be most effective in reducing fat mass and increasing lean mass when combined with enhanced physical activity. CLA intake was not always associated with significant reductions in body weight, which is consistent with data from animal studies.

Safety Evaluation of CLA-Mixed Isomers A large number of published studies—including traditional toxicology studies and extensive human trials—have assessed the safety of CLA (50:50 mixture). CLA is the subject of 32 clinical studies in which the 50:50 mixture of isomers was evaluated. A comprehensive review of the clinical data has demonstrated that consumption of 50:50 CLA isomers at levels up to 6 g/day for up to 1 year (Larsen et al., 2006; Whigham et al., 2004) and 3.4 g/day for up to 2 years (Gaullier et al., 2004, 2005, 2007) is safe and has no significant effects on cardiovascular parameters (lipid metabolism, markers of inflammation, and markers of oxidative stress), insulin sensitivity and glucose, and milk fat deposition (Cognis GmbH, 2007). Although most consumers for CLA products are expected to be adults, the safety evaluation has considered potential use among children and did not find any potential adverse effects among children at the recommended use level. Pre-clinical data have demonstrated an absence of significant toxicological, mutagenic, or reproductive and developmental effects. Subchronic and chronic studies in rats demonstrate that CLA at 2,433 and 2,728 mg/kg body weight/day for males and females, respectively, for periods of 13 weeks to 18 months, produce no significant adverse effects. Reproductive and developmental toxicity studies in rats and pigs demonstrate a lack of adverse effects on maternal food consumption and body weight, litter size, or offspring growth and development following exposure to CLA


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(0.25–2% in the diet, equivalent to 250–500 mg/kg body weight/day) throughout gestation, lactation, and/or during the postweaning period. In vitro assays demonstrate an absence of mutagenicity or genotoxicity (reviewed in Ritzenthaler et al., 2001, Cognis GmbH, 2007, and Campbell and Kreider, 2008). Based on the clinical data, toxicological data, and the history of dietary consumption of CLA, an expert panel concluded in 2007 that estimated consumption of 50:50 CLA isomers is safe within the meaning of the FDA regulations for use as a food ingredient at levels of up to 1.5 g CLA per serving, with expected use of approximately 2 servings per day (Cognis GmbH, 2007). FDA agreed with the expert panel’s conclusion in July 2008 and issued no-question letter to the petitioners, one of which is Cognis GmbH (FDA, 2008); thus, Cognis’ CLA-mixed isomers achieved the so-called FDA-notified GRAS status.

Regulatory Status Labeling Commercial CLA can be labeled as CLA or conjugated linoleic acid. CLA is not considered as trans fat according to FDA rulings (68 Fed. Reg. 41433, 41462, 2003). Because commercial high-quality CLA oil, such as the Tonalin CLA TG80, is derived from highly refined natural safflower oil, it is also exempt from allergen labeling requirement. CLA is fatty acid; thus, the calorie calculation for nutrition labeling is based on its fat content. In the case of Cognis’ Tonalin CLA, the TG 80 (100% fatty acids) = 9 kcal/g, 60 WDP (80% fatty acids) = 7 kcal/g, 35 WDP (67% fatty acids) = 6 kcal/g.

Claims The claims on CLA’s effect on body composition were documented by several patents and licensed to a couple of CLA manufacturers, such as Cognis GmbH, the manufacturer of Tonalin CLA. The following structure function claims can be used for either foods or dietary supplements: Clinical and laboratory research indicates that Tonalin CLA r helps reduce body fat, r maintains lean body mass,


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r improves body composition, r increases lean body mass, r enhances lean body mass.

Application of CLA in Functional Foods Cognis’ CLA is FDA GRAS. It is intended for use in specific foods within the following general food categories: beverages and beverage bases, grain and pasta products, milk and milk products, and processed fruits and fruit juices. Specifically, these food applications are as follows: r r r r r r r r

Coffee creamers (only for Cognis’ Tonalin CLA) Chocolate (only for Cognis’ Tonalin CLA) Milk-based and fruit-based beverages Soy milk beverages Meal-replacement beverages and bars Milk and flavored milk products Yogurt products Fruit juice products

The level to be added into foods is at a level of up to 1.5 g CLA per labeled serving and up to 2 servings a day as a total recommended daily intake of 3 g CLA/day.

CLA Forms There are a variety of CLA forms available from major suppliers for nearly any type of food applications. For instance, Cognis offers the r Tonalin range of CLA products in multiple concentrations and forms to meet a wide range of formulation requirements, such as 80% triglyceride or free fatty acids oil, 60% encapsulated water dispersible powder, and 35% acid-stable water dispersible powder. Additionally, a customized wet emulsion form is available for beverage applications. Table 1.1 lists the product forms available at Cognis GmbH. When CLA oil used, it can replace existing fat or oil in food formula. If developers need to blend the CLA with other dry ingredients, a powder form is more appropriate. When CLA powder is used, food manufacturers must list in the ingredient statement any carriers contained in powders (i.e., gum arabic, maltodextrin).


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Table 1.1.

The different forms of CLA producta

CLA Product Forms r

Tonalin TG 80

r

Tonalin 35 WDP

r

Tonalin 40 WDP

r

Tonalin 60 WDP

a Provided

Description

Food Applications

78–84% as CLA triglyceride, transparent, colorless to slightly yellow liquid at room temperature with characteristic taste/odor 32–38% CLA cold water dispersible powder, fine, free flowing, cold water dispersible white powder with characteristic taste/odor, gum acacia as carrier 37–42% CLA water dispersible powder, fine, free flowing, cold water dispersible white to off-white powder with characteristic taste/odor, modified food starch derived from waxy maize as carrier 53–62% CLA water dispersible powder, fine, free flowing, cold water dispersible, white to off-white powder with characteristic taste/odor, milk powder as carrier

Oil-based food products, spreads, dairy, dressings

Cloudy beverages, baked goods, dairy, cereals, bars

Dry powder mixes, powdered drink mixes, formulas as chewable tablet and two piece capsules Dairy beverages, yogurts, baked goods, cereals, bars

by Cognis GmbH.

Stability CLA, in general, is very stable and is not impacted by heat treatment and/or acid environments. The stability of CLA has been monitored by following the fatty acid profile, c9,t11 and t10,c12 isomer distribution, color (Hazen or Gardner), acid value, peroxide value, glyceride composition, and nonlipid components under a variety of storage conditions (e.g., plastic, steel, and glass containers). For storage of greater than 1 month, CLA should be stored in the dark in an air-free environment and not exposed to elevated temperatures (>25◦ C) or strong odors. Under the appropriate storage conditions, CLA triglycerides oil was completely stable in airtight steel drums over 24 months. In addition, CLA is an



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anhydrous system and will not support microbial growth. CLA is stable in various food matrices (orange juice, milk, yogurt, and nutrition bars) and following pasteurization and ultrahigh temperature (UHT) treatment. As far as interaction with other ingredients is concerned, the avoidance of pro-oxidants is recommended.

Sensory Impact CLA is a bland tasting product with a slight characteristic flavor that can be masked by various flavoring agents. When used and handled in accordance with suppliers’ recommendations, the impact on sensory characteristics should be minimal.

References Villegas JA, Román JL, Gonzálvez ABM, Luque A. Effect of physical activity and ingestion of CLA enriched milk on health overweight subjects. Rev Esp Obes 2007; 5 (2): 109–118. Banni S. Conjugated linoleic acid metabolism. Curr Opin Lipid 2002; 13 (3): 261–266. Berven G, Bye A, Hals O, Blankson H, Fagertun H, Thom E, Wasstein J, Gudmundsen O. Safety of conjugated linoleic acid (CLA) in overweight or obese human volunteers. Eur J Lipid Sci Technol 2000; 102: 455–462. Bhattacharya A, Banu J, Rahman M, Causey J, Fernandes G. Biological effects of conjugated linoleic acids in health and disease. J Nutr Biochem 2006; 17 (12): 789–810. Blankson H, Stakkestad JA, Fagertun H, Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat mass in overweight and obese humans. J Nutr 2000; 130, 2943–2948. Brown JM, Boysen MS, Jensen SS, Morrison RF, Storkson J, Lea-Currie R, Pariza M, Mandrup S, McIntosh MK. Isomer-specific regulation of metabolism and PPAR γ signaling by CLA in human preadipocytes. J Lipid Res 2003; 44: 1287–1300. Campbell B, Kreider RB. Conjugated linoleic acids. Curr Sports Med Rep 2008; 7 (4): 237–241.


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Choi Y, Kim YC, Han YB, Park Y, Pariza MW, Ntambi JM. The trans10,cis-12 isomer of conjugated linoleic acid downregulates stearoylCoA desaturase 1 gene expression in 3T3-L1 adipocytes. J Nutr 2000; 130 (8): 1920–1924. Close RN, Schoeller DA, Watras AC, Nora EH. Conjugated linoleic acid supplementation alters the 6-mo change in fat oxidation during sleep. Am J Clin 2007; 86: 797–804. Cognis GmbH. GRAS notification dossier. GRN 232. 2007. Evans M, Geigerman C, Cook J, Curtis L, Kuebler B, McIntosh M. Conjugated linoleic acid suppresses triglyceride accumulation and induces apoptosis in 3T3-L1 preadipocytes. Lipids 2000; 35 (8): 899– 910. FDA. FDA response letter to GRN 232. 2008. Fischer-Posovszky P, Kukulus V, Zulet MA, Debatin KM, Wabitsch M. Conjugated linoleic acids promote human fat cell apoptosis. Horm Metab Res 2007; 39 (3): 186–191. Gaullier JM, Breven G, Blankson H, Gudmondsen O. Clinical trial results support a preference for using CLA preparations enriched with two isomers rather than four isomers in human studies. Lipids 2002; 37: 1019–1025. Gaullier JM, Halse J, Hoivik HO, Hoye K, Syvertsen C, Nurminiemi M, Hassfeld C, Einerhand A, O’Shea M, Gudmundsen O. Six months supplementation with conjugated linoleic acid induces regional-specific fat mass decreases in overweight and obese. Br J Nutr 2007; 97 (3): 550–560. Gaullier JM, Halse J, Hoye K, Kristiansen K, Fagertun H, Vik H, Gudmundsen O. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr 2004; 79 (6): 1118–1125. Gaullier JM, Halse J, Hoye K, Kristiansen K, Fagertun H, Vik H, Gudmundsen O. Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans. J Nutr 2005; 135: 778– 784. Gavino VC, Gavino G, Leblanc MJ, Tuchweber B. An isomeric mixture of conjugated linoleic acids but not pure cis-9, trans-11-octadecadienoic



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acid affects body weight gain and plasma lipids in hamsters. J Nutr 2000; 130: 27–29. Hargrave KM, Li C, Meyer BJ, Kachman SD, Hartzell DL, Della-Fera MA, Miner JL, Baile CA. Adipose depletion and apoptosis induced by trans-10, cis-12 conjugated linoleic Acid in mice. Obes Res 2002; 10 (12): 1284–1290. Henriksen EJ, Teachey MK, Taylor ZC, Jacob S, Ptock A, Kramer K, Hasselwander O. Isomer-specific actions of conjugated linoleic acid on muscle glucose transport in the obese Zucker rat. Am J Physiol 2003; 285 (1): E98–E105. Ip C, Dong Y, Ip MM, Banni S, Carta G, Angioni E, Murru E, Spada S, Melis MP, Saebo A. Conjugated linoleic acid isomers and mammary cancer prevention. Nutr Cancer 2002; 43 (1): 52– 58. Kamphuis MM, Lejeune MP, Saris WH, Westerterp-Plantenga MS. Effect of conjugated linoleic acid supplementation after weight loss on appetite and food intake in overweight subjects. Eur J Clin Nutr 2003a; 57 (10): 1268–1274. Kamphuis MM, Lejeune MP, Saris WH, Westerterp-Plantenga MS. The effect of conjugated linoleic acid supplement after weight loss on body weight regain, body composition, and resting metabolic rate in overweight subjects. Int J Obes Relat Metab Disord 2003b; 27 (7): 840– 847. Kang KH, Liu W, Albright KJ, Park Y, Pariza MW. trans-10,cis12 CLA inhibits differentiation of 3T3-L1 adipocytes and decreases PPAR gamma expression. Biochem Biophys Res Comm 2003; 303 (3): 795–799. Kreider RB, Ferreira MP, Greenwood M, Wilson M, Almada AL. Effects of conjugated linoleic acid supplementation during resistance training on body composition, bone density, strength, and selected hematological markers. J Strength Cond Res 2002; 16 (3): 325– 334. LaRosa PC, Miner J, Xia Y, Zhou Y, Kachman S, Fromm ME. Trans-10, cis-12 conjugated linoleic acid causes inflammation and delipidation of white adipose tissue in mice: a microarray and histological analysis. Physiol Genomics 2006; 27 (3): 282– 294.


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Larsen TM, Toubro S, Gudmundsen O, Astrup A. Conjugated linoleic acid for 1y does not prevent weight or body fat regain. Am J Clin Nutr 2006; 83: 606–612. Laso N, Bruque E, Vidal J, Ros E, Arnaiz JA, Carne X, Vidal S, Mas S, Deulofeu R, Lafuente A. Effect of milk supplementation with conjugated linoleic acid (isomers cis-9, trans-11 and trans-10, cis-12) on body composition and metabolic syndrome components. Br J Nutr 2007; 11: 1–8. Nagao K, Wang YM, Inoue N, Han SY, Buang Y, Noda T, Kouda N, Okamatsu H, Yanagita T. The 10trans, 12cis isomer of conjugated linoleic acid promotes energy metabolism in OLETF rats. Nutrition 2003; 19 (7–8): 652–656. Nazare JA, de la Perriere AB, Bonnet F, Desagne M, Peyrat J, Maitrepierre C, Louche-Pelissier C, Bruzeau J, Goudable J, Lassel T, Vidal H, Laville M. Daily intake of conjugated linoleic acid- enriched yoghurts: effects on energy metabolism and adipose tissue gene expression in healthy subjects. Br J Nutr 2007; 97 (2): 273–280. Noone EJ, Roche HM, Nugent AP, Gibney MJ. The effect of dietary supplementation using isomeric blends of conjugated linoleic acid on lipid metabolism in healthy human subjects. Br J Nutr 2002; 88: 243– 251. Newton RL, Jr, Alfonso A, York-Crowe E, Walden H, White MA, Ryan D, Williamson DA. Comparison of body composition methods in obese African-American women. Obesity 2006; 14 (3): 415–422. Pariza MW, Park Y, Cook ME. The biologically active isomers of conjugated linoleic acid. Prog Lipid Res 2001; 40 (4): 283–298. Park Y, Albright KJ, Liu W, Storkson JM, Cook ME, Pariza MW. Effect of conjugated linoleic acid on body composition in mice. Lipids 1997; 32 (8): 853–858. Park Y, Storkson JM, Albright KJ, Liu W, Pariza MW. Evidence that the trans-10,cis-12 isomer of conjugated linoleic acid induces body composition changes in mice. Lipids 1999; 34 (3): 235–241. Pinkoski C, Chilibeck PD, Candow DG, Esliger D, Ewaschuk JB, Facci M, Farthing JP and Zello GA. The effects of conjugated linoleic acid supplementation during resistance training. Med Sci Sports Exerc 2006; 38/2: 339–348.



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Ritzenthaler KL, McGuire MK, Falen R, Shultz TD, Dasgupta N, McGuire MA. Estimation of conjugated linoleic acid intake by written dietary assessment methodologies underestimates actual intake evaluated by food duplicate methodology. J Nutr 2001; 131 (5): 1548–1554. Sébédio JL, Chardigny JM, Beredeaux O. Metabolism of conjugated linoleic acids. In: Sébédio JL, Christie WW, Adlof R (eds.). Advances in Conjugated Linoleic Acid Research, Vol. 2. AOCS Press, Champaign, IL, 2003, pp. 259–266. Steck S, Chalecki A, Miller P, Conway J, Austin G, Hardin J, Albright C, Thuillier P. Conjugated linoleic acid supplementation for 12 weeks increases lean body mass in obese humans. J Nutr 2007; 137: 1188–1193. Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat in healthy exercising humans. J Int Med Res 2001; 29: 392–396. Tsuboyama-Kasaoka N, Takahashi M, Tanemura K, Kim HJ, Tange T, Okuyama H, Kasai M, Ikemoto S, Ezaki O. Conjugated linoleic acid supplementation reduces adipose tissue by apoptosis and develops lipodystrophy in mice. Diabetes 2000; 49 (9): 1534–1542. Watras AC, Buchholz, AC, Close RN, Zhang Z, Schoeller, DA. The role of conjugated linoleic acid in reducing body fat and preventing holiday weight gain. Int J Obes 2006; 31 (3): 481–487. Whigham LD, O’Shea M, Mohede IC, Walaski HP, Atkinson RL. Safety profile of conjugated linoleic acid in a 12-month trial in obese humans. Food Chem Toxicol 2004; 42 (10): 1701–1709. Whigham LD, Watras AC, Schoeller DA. Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans. Am J Clin Nutr 2007; 85: 1203–1211.


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CHAPTER 2

Appetite Suppression Effects of PinnoThinTM (Korean Pine Nut Oil) Dr. Corey E. Scott, PhD

Abstract The use of natural appetite suppressants to affect satiety and food intake may be an effective strategy to help reduce worldwide weight gain and obesity trends. PinnoThinTM is a natural oil pressed from Korean pine nuts, which is uniquely high in pinolenic acid and works as an appetite suppressant. In randomized, placebo-controlled, double-blind clinical trials, PinnoThinTM triglyceride (TG) or the natural metabolite free fatty acid (FFA) form has shown the ability to significantly increase key satiety hormones cholecystokinin (CCK) and glucagonlike peptide-1 (GLP-1), significantly reduce ad libitum food intake, and affect self-reported feelings of satiety (visual analogue scales). PinnoThinTM TG can be incorporated easily into liquid foods, such as flavored milk or yogurt, and is also available in a powdered form, which can be incorporated into other food matrices. Given its noted effects on satiety, PinnoThinTM can be a promising food ingredient or supplement to help promote weight management via appetite suppression.

Introduction As worldwide obesity rates continue to rise, it is imperative to develop key strategies that are both effective and applicable to the general population to help prevent weight gain. Two prominent factors that can 25


26

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contribute to weight gain are a lack of physical exercise and a surplus of energy intake. Estimations of energy balance suggest that an increase in daily caloric intake of 50–100 kcal more than energy expenditure can result in a yearly increase in body weight of 1–2 kg, contributing to the development of obesity (Brown et al., 2005). One strategy to reduce the amount of excess energy and food intake that can lead to weight gain is via the use of natural ingredients that can regulate appetite. Human appetite is controlled by a complex feedback system that regulates hunger, satiety, and satiation. Hunger can be defined as the desire for food intake whereas satiation is the signal to terminate food intake. Satiety is defined as the time period between meals in which there is no food intake. Feelings of hunger, satiation, and satiety are all regulated by the nervous and the hormonal system (Wynne et al., 2005). When food is consumed and digested, several key gastrointestinal hormones are released to alert the brain of the presence of food in the gut and to eventually reduce food intake. Key satiety hormones that regulate food intake are cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), ghrelin, and peptide tyrosine tyrosine (PYY) (Ballantyne, 2006; Burton-Freeman et al., 2004; de Graaf et al., 2004; Degen et al., 2001; Greenman et al., 2004; Gutzwiller et al., 2004; Verdich et al., 2001). CCK is released in the proximal small intestine (duodenum) into the bloodstream in response to fatty acids and protein (Burton-Freeman et al., 2004) (Fig. 2.1).

Appetite

CCK GLP-1 PYY

Figure 2.1. Activity of satiety hormones CCK, GLP-1, and PYY to decrease appetite.


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Appetite Suppression Effects of PinnoThinTM

27

CCK release has long been associated with effects on appetite with higher concentrations producing more effects on appetite (Beglinger and Degen, 2004; Burton-Freman et al., 2002; Degen et al., 2001; Drewe et al., 1992; Gutzwiller et al., 2004; Hildebrand et al., 1998; Hopman et al., 1985; Lieverse et al., 1994). In addition, infusions of exogenous CCK in humans have been shown to reduce food intake and enhance satiety (Geary et al., 1992; Greenough et al., 1998; Gutzwiller et al., 2000; Kissileff et al., 1981). GLP-1 and PYY also work to decrease appetite and are released in the distal small intestine (ileum) of the gut when carbohydrates and fats are present (Ballantyne, 2006; de Graaf et al., 2004; Frost et al., 2003; Greenman et al., 2004; Kong et al., 1999; Lavin et al., 1998; Ranganath et al., 1996; Thomsen et al., 2003; Verdich et al., 2001). Similar to CCK infusions in humans, exogenous GLP-1 infusions have been shown to significantly reduce food intake at ad libitum meals by decreasing hunger and enhancing satiety (Flint et al., 1998, 2001; Gutzwiller et al., 1999a, 1999b; Halton and Hu, 2005; Naslund et al., 1998, 1999). Ghrelin is produced by the stomach and opposes the actions of CCK and GLP-1 as it induces hunger and increases appetite (Greenman et al., 2004). The roles of macronutrients (fats, carbohydrates, and proteins) in appetite suppression via satiety hormone release have been extensively studied. Of these, it has been suggested that protein and fiber-rich foods produce strong satiety responses (Halton and Hu, 2005; Slavin, 2005). Fat intake releases satiety hormones CCK and GLP-1, which can affect satiety despite there being a relationship between high fat intake and increased weight gain (Blundell et al., 1995). This apparent contradiction may be explained in part by the type of fat that is consumed. The effects of fats on satiety and food intake are related to chain length and degree of saturation (number of double bonds). In nature, fats exist as forkshaped molecules that consist of three fatty acids bound to a glycerol backbone. When fats are ingested, the triglyceride is broken down by lipases yielding free fatty acids (FFAs) (Fig. 2.2). FFAs trigger the release of satiety hormones, more so than triglycerides (Little et al., 2007). It has been demonstrated that long-chain FFA (greater than 14 carbons) produced greater effects on hunger and plasma CCK levels than medium-chain FFA (12–14 carbons) (Feinle et al., 2001). In addition, only fatty acids with chain lengths ≥ 12 carbons are capable of releasing significant amounts of CCK (Beglinger and Degen, 2004; Burton-Freman et al., 2002). Moreover, duodenal infusions of FFA of a chain length of 12 carbons produced more potent effects on food intake, appetite expression, and CCK and GLP-1 release compared with a FFA


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Lipid based ingredients O HO

O

O

H2C O O

Lipase

HC O O

HO Free fatty acids

H2C O Triglyceride

H3C

O

+

HC O H3C

Monoglyceride

Figure 2.2. Enzymatic hydrolysis of triglycerides into free fatty acids and a monoglyceride during human digestion.

of chain length of C10 (Feltrin et al., 2004). In terms of saturation and effects on appetite, polyunsaturated fatty acids (PUFAs, fats with one or more double bonds) exert a stronger effect on appetite expression than monounsaturated (MUFA, fats with one double bond) and saturated (SFA, fats with no double bonds) (Lawton et al., 2000). GLP-1 release is also affected by the degree of saturation and is released by MUFA rather than SFA in response to high-fat meals (Thomsen et al., 1999, 2003). Thus, selective intakes of oils containing longer chain fats with high degrees of unsaturation can have implications for appetite regulation and long-term weight management (Halford, 2007). One such oil with a high concentration of long-chain PUFA that may influence satiety hormones is PinnoThinTM . PinnoThinTM is a natural oil pressed from Korean pine nuts (Pinus Koraiensis). Korean pine nut oil is derived from the nuts of the native Korean pine tree. This tree grows in Korea, Japan, Siberia, and China (Manchuria). Pine nuts consist of about 60% oil by weight and have long been widely consumed in popular dishes and as condiments in many geographical areas. Pine nut oil consists of 92% of PUFAs and MUFAs, mainly pinolenic acid (C18:3), linoleic acid (C18:2), and oleic acid (C18:1) (Wolff et al., 2000) (Fig. 2.3). PinnoThinTM is unique in that it contains a large concentration of pinolenic acid, which makes up approximately 14% of the total fatty acids, whereas other pine nuts contain approximately 1–2% of pinolenic acid (Wolff et al., 2000). The high concentration of PUFA and the uniquely high content of pinolenic acid lead to the hypothesis that PinnoThinTM intake can reduce appetite by an induction of satiety hormones. In peer-reviewed, published human clinical studies (Hughes et al., 2008; Pasman et al., 2008), PinnoThinTM supplementation has shown the ability


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29

O HO Oleic acid O HO Linoleic acid O HO Pinolenic acid

Figure 2.3. Unsaturated fatty acids found in PinnoThinTM .

to influence satiety and food intake and can be an integral part of weight management.

Effects of PinnoThinTM on In Vitro CCK Release PinnoThinTM was first evaluated for its effects on releasing the satiety hormone CCK in cell culture. PinnoThinTM and several other common fatty acids such as capric acid (C10), oleic acid (C18:1), linoleic acid (C18:2), α-linoleic acid (C18:2), and oil from Italian stone pine nut (oleic, linoleic, and pinolenic (1.2%)) were added to a well-established murine enteroendocrine tumor cell line, STC-1, at 50 µM concentrations for 60 minutes and evaluated for the release of CCK (Pasman et al., 2008). PinnoThinTM produced the greatest release in CCK (493 pg/mL), and as expected, capric acid, a small-chain fatty acid, which is more quickly absorbed in the human body and elicits a poorer CCK response, produced the least (46 pg/mL) (Fig. 2.4). Oleic, linoleic, and α-linoleic acids produced similar amounts of CCK relative to each other, which were 145, 138, and 124 pg/mL, respectively, but much lower than that of PinnoThinTM . Italian stone pine nut oil produced a very small amount of CCK in this evaluation, which was 62 pg/mL. The fatty acid profile of PinnoThinTM and Italian stone pine nuts are similar although PinnoThinTM is much more concentrated in pinolenic acid, which may suggest the large differences in the observed in vitro CCK release.


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30


Lipid based ingredients 600

CCK release (pg/mL)

500

400

300

200

100

0 PinnoThin

Italian stone pine nut

Oleic acid

Linoleic acid Alpha linoleic Capric acid acid

Figure 2.4. The effects of PinnoThinTM and other fatty acids on CCK release from STC-1 cell lines.

In Vivo Effects of PinnoThinTM on Satiety Hormones and Subjective Measures of Satiety (VAS) The observation that PinnoThinTM increased in vitro CCK to a greater extent than many other commonly consumed fats in the diet led to the hypothesis that PinnoThinTM may increase satiety hormones and affect appetite feelings in humans. For this study, 18 overweight, postmenopausal women were chosen to participate in a randomized, double-blind, placebocontrolled, crossover trial (Pasman et al., 2008). The volunteers had a median BMI of 27.4 kg/m2 , median age of 55 years, and median weight of 76.7 kg. The volunteers reported to the laboratory after an overnight fast and a cannula was inserted in the forearm in an antecubital vein for blood sampling. Each of the volunteers consumed a light breakfast consisting of two pieces of white bread with marmalade and no additional fat and each received 3 g of PinnoThinTM TG (triglyceride), 3 g of PinnoThin FFA (natural metabolite FFA form), or 3 g of olive oil (placebo) in the form of softgel capsules that they consumed with the breakfast and a glass of water.


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After capsules and breakfast were taken, blood was sampled to measure satiety hormones CCK, GLP-1, Ghrelin, and PYY at t = 0, 30, 60, 90, 120, 180, and 240 minutes after start of breakfast. Appetite sensations were evaluated using visual analogue scales (VASs) for “hunger,” “fullness,” “desire to eat,” and “prospective food consumption” (Flint et al., 2000; Stubbs et al., 2000). The VASs consisted of horizontal lines, with each end expressing the most positive or negative sensation (i.e. I am not hungry at all/I am extremely hungry). Subjects drew a vertical line on the horizontal line corresponding to their appetite sensation. These procedures were followed for each treatment on three test days, with a washout period of 1 week between treatments. With respect to the effects of PinnoThinTM on satiety hormones, CCK release was significantly higher with PinnoThinTM FFA than with placebo at 30, 90, 120, and 180 minutes (Fig. 2.5).

pmol/L

CCK

1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0

* **

0

30

60

*

* **

*

90 Minutes

120

180

240

120

180

240

GLP-1

16

*

14

pmol/L

12 10 8 6 4 2 0

0

30

60

90 Minutes

Figure 2.5. The effects of PinnoThinTM FFA •, PinnoThinTM TG , and olive oil placebo on CCK and GLP-1 release. * indicates p < 0.05 for PinnoThinTM FFA, ** indicates p < 0.05 for PinnoThinTM TG.


32

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CCK release was also significantly higher at 60 and 120 minutes with PinnoThinTM TG compared with placebo. The CCK area under the curve (AUC) for PinnoThinTM FFA was 60.3% higher and for PinnoThinTM TG 22.0% higher than the CCK AUC for placebo (p < 0.0001). The overall response curves for CCK were significantly different between the treatments. The maximal concentration (Cmax ) reached for PinnoThin FFA was 2.0 ± 0.43 pmol/L; for PinnoThinTM TG, 1.45 ± 0.23 pmol/L; and for placebo, 1.08 ± 0.15 pmol/L (p < 0.01). The other satiety hormone studied, GLP-1 (Fig. 2.5), also showed overall different response curves between treatments. GLP-1 release was significantly higher using PinnoThinTM FFA than using placebo at 60 minutes (p < 0.05). GLP-1 AUC was 25.1% higher after the PinnoThinTM FFA than with placebo (p < 0.01). GLP-1 release takes place in the distal colon whereas CCK release takes place in the first parts of the small intestine that suggests why GLP-1 release took longer than CCK release. The effects of PinnoThinTM TG on GLP-1 release were similar to placebo. Similar effects on ghrelin were observed with PinnoThinTM FFA, PinnoThinTM TG, and placebo. At 60, 180, and 240 minutes, the PYY concentrations after PinnoThinTM FFA was higher than placebo and the AUC was 16.2% higher for PinnoThinTM FFA versus placebo (p < 0.01). There were no significant effects of PinnoThinTM TG on PYY release versus placebo. Regarding VAS scoring, “prospective food consumption” at 30 minutes was 36% lower for PinnoThinTM FFA compared to placebo (p < 0.01) (Fig. 2.6). This study showed that PinnoThinTM can influence satiety in humans by increasing the release of hormones that regulate appetite and affecting subjective measures of satiety such as VAS scores (prospective food intake). From this study, both forms of PinnoThinTM showed efficacy, with the natural metabolite PinnoThinTM FFA showing greater efficacy in releasing satiety hormones and influencing VAS scores. This is consistent with other studies showing that FFA triggers the release of CCK (Cox et al., 2004; Guimbaud et al., 1997; Hildebrand et al., 1998). Also, this study found effects with only 18 people and perhaps a larger population may have yielded greater differences in VAS scores and satiety hormones. Although effects of PinnoThinTM were shown for key satiety hormones, CCK and GLP-1, a consistent effect of PinnoThinTM on PYY and ghrelin hormones was not found. A lack of an effect of fat intake on ghrelin was also reported by Poppitt and coworkers (Poppitt et al., 2006) showing that high-fat meals and fatty acid saturation levels had no differential effect on ghrelin levels in healthy men.


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33

70

60

50

Score

40

30

20

* *

10

0 0

30

60

90

120

150

180

210

240

Minutes

Figure 2.6. The effects of PinnoThinTM FFA •, PinnoThinTM TG , and olive oil placebo on prospective food intake. * indicates p < 0.05 for PinnoThinTM FFA.

The Effects of PinnoThinTM on Ad Libitum Food Intake Given the previous study that PinnoThinTM can increase satiety hormones and also affect subjective satiety scores (VAS) in humans, a study was performed to evaluate the effects of PinnoThinTM administration on subsequent ad libitum (at will) food and caloric intake (Hughes et al., 2008). For this evaluation, 42 nonsmoking, healthy overweight women (median BMI of 27.4 kg/m2 , median age of 33.8 years, median weight of 73.9 kg) were included in a double-blind, placebo-controlled, crossover study and randomized to receive five treatments, placebo (olive oil), 2 g PinnoThinTM TG, 4 g PinnoThinTM TG, 6 g PinnoThinTM TG, and 2 g PinnoThinTM FFA (natural metabolite) administered as softgel capsules. On each test day, participants came into the study site where they consumed a fixed-load breakfast (496 kcal) consisting of cereal, milk,


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Study day

8:30 am Fixed breakfast

1:00 pm Ad libitum lunch

5:00 pm Ad libitum supper

12:30 pm PinnoThin capsules

Figure 2.7. Food-intake study design.

white bread toast, orange juice, and a hot drink. Three and a half hours later and 30 minutes prior to the ad libitum lunch, six capsules containing either the placebo oil or doses of PinnoThinTM were provided with 200 mL water to the volunteers. After 30 minutes, an ad libitum lunch consisting of several different food choices such as sandwich items, pizza, and dessert items was served with water. The volunteers were instructed to consume as much as they liked from the choice of foods offered, taking as long as they wished, and signaling when they had finished. Four hours later, participants returned and were served a hot ad libitum evening meal consisting of a pasta dish. Similar to the lunch meal, volunteers were asked to consume as much as they desired, taking as long as they wished and signaling when they had finished. The study design is outlined in Fig. 2.7. The study found that the PinnoThinTM FFA intake before lunch was associated with a reduction in the amount of food and energy intake at the lunch meal. Two grams of PinnoThinTM FFA significantly reduced intake of food by 9% at the lunch meal (347.9 g PinnoThinTM vs. 380.2 g olive oil placebo, p = 0.029) (Fig. 2.8). Furthermore, caloric intake at lunch was reduced by 7% (656.2 kcal PinnoThinTM vs. 706.1 kcal olive oil placebo, p = 0.09), which corresponds to roughly a 50-kcal reduction. Although this reduction narrowly missed statistical significance most likely due to lack of power, a reduction of 50 kcal is physiologically relevant. Brown et al. (2005) have suggested that the average weight gain in a female population equates with an energy imbalance of only 10–40 kcal/day. No effects were seen for food or caloric intake at the dinner meal for the PinnoThinTM FFA versus the placebo (530.2 g and 1,024.2 kcal vs. 521.4 g and 1,002.4 kcal, respectively; p = ns) indicating that the volunteers did not compensate for the reduced caloric and food intake observed at lunch. The effects on food intake of PinnoThinTM TG at the doses tested were similar to that of olive oil, although PinnoThinTM FFA in the natural


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35

Food intake (g)

400 375

*

350 325

Caloric intake (kcal)

300 Placebo

PinnoThin FFA

Placebo

PinnoThin FFA

750 700 650 600 550

Figure 2.8. The effects of PinnoThinTM FFA on food intake (g) and caloric intake (kcal) during an ad libitum lunch. * denotes statistical difference (p < 0.05)

metabolite form was efficacious at 2 g.The lack of a significant effect for the PinnoThinTM TG may be explained by the timing of the administration rather than dosage. PinnoThinTM can affect satiety by increasing the release of satiety hormones CCK and GLP-1 (Pasman et al., 2008). In order to trigger the release of satiety hormones, PinnoThinTM TG must first be metabolized into FFA. In a previous study using both PinnoThinTM TG and PinnoThinTM FFA, the peak release in CCK took longer for the TG compared to the FFA (60 minutes rather than 30 minutes) (Pasman et al., 2008). In this food-intake study, the PinnoThinTM TG was administered 30 minutes prior to the ad libitum lunch and not 60 minutes where a peak increase in CCK by PinnoThinTM TG has been previously observed (Pasman et al., 2008). This study showed that the natural metabolite form of PinnoThinTM , PinnoThinTM FFA can reduce food and caloric intake in healthy overweight women. The lack of significant effects of PinnoThinTM TG on food intake remains unclear and more research is needed to determine how PinnoThinTM TG affects satiety. Future studies are underway in larger groups of people using various food applications that may make


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PinnoThinTM TG more bioavailable and produce stronger effects on satiety and food intake. In other studies, FFA release from PinnoThinTM TG has been observed in in vitro digestion models and also in plasma isolated from individuals who had consumed a beverage containing 3 g of PinnoThinTM TG (unpublished data). Thus, FFA from PinnoThinTM TG are bioavailable and may require sufficient time before a meal to affect food intake.

Food Applications PinnoThinTM is available as a natural oil in triglyceride form and can be applied to a wide range of food products. The recommended dosage of PinnoThinTM for satiety benefits is 3 g per serving. Extensive tests with PinnoThinTM have been performed to test the effect of several standard processing steps including homogenization, UHT treatment, pasteurization, sterilization, baking, extrusion, molding, fermentation, and acidification. These processing steps do not affect PinnoThinTM in concentration and sensory parameters. PinnoThinTM can also be taken as a supplement in a softgel form. For food products, PinnoThinTM is most recommended for liquid food products such as flavored milk, yogurt, and beverages, and for products such as dressings and other fat-based products such as fat spreads. PinnoThinTM has also been successfully applied to bakery products including cookies and nutritional bars. Incorporating PinnoThinTM in food products can be done by replacing or by mixing the existing fat phase with PinnoThinTM . In aqueous solutions, it may be useful to add PinnoThinTM as an emulsion. Emulsions can be made by adding the oil phase (PinnoThinTM and/or others) to the water phase (e.g., water, yogurt, milk) under continuous mixing followed by homogenization. After homogenization, a heat treatment can be applied to extend the shelf life of the product. PinnoThinTM is also available as a microencapsulated powder containing 60% PinnoThinTM TG. This product can be used in instant products such as powdered shakes, meal replacer shakes, and so on. The PinnoThinTM powder is also recommended for food products with relatively low water activities such as nutritional bars, cookies, bread, instant powders, and so on. The stability of PinnoThinTM in food products is comparable to other PUFAs. PUFAs are most sensitive to oxidation. Oxidation of fats can have a negative impact on the quality of the final product, such as formation of


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off-flavors, discoloring, change in texture, and formation of free radicals. It is best to avoid the following factors where possible, such as exposure to oxygen, heat, light, and transition metals. PinnoThinTM contains mixed tocopherols to increase the stability of the oil.

History of Pine Nut Consumption Pine nuts have long been constituent parts of the diets of many cultures, particularly in the Mediterranean and Asian regions, and they are now also consumed very widely outside these geographical areas. To date, no published studies are known or available, which shows that daily human exposure to Korean pine nut oil is unsafe and causes adverse events. Historical use of pine nut oil in foods, at levels of up to 7.5 g/day, has not been associated with adverse events. In addition, pine seeds are commonly used in a variety of foods including breads, ice cream, and cookies, and so an exposure could potentially exceed 7.5 g/day. PinnoThinTM has been tested in two human clinical studies with up to 6 g doses with no reported adverse events versus a placebo oil.

Conclusion PinnoThinTM is an all-natural appetite suppressant that has been clinically shown to affect satiety. In human clinical studies, PinnoThinTM significantly increased satiety hormones that play an essential role in appetite suppression. The effects of PinnoThinTM were further confirmed in a subsequent human trial, which showed that PinnoThinTM FFA can reduce food and caloric intake. Taken together, the effects of PinnoThinTM on satiety can play a key role in the overall strategy for weight management.

References Ballantyne GH. Peptide YY (1–36) and peptide YY (3–36). Part I: distribution, release and actions. Obes Surg 2006;16:651–658. Beglinger C, Degen L. Fat in the intestine as a regulator of appetite—role of CCK. Physiol Behav 2004;83:617–621. Blundell JE, Cotton JR, Delargy H, Green S, Greenough A, King NA, Lawton CL. The fat paradox: fat-induced satiety signals versus high-fat over-consumption. Int J Obes 1995;19:832–835.


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Brown WJ, Williams L, Ford JH, Ball K, Dobson AJ. Identifying the energy gap: magnitude and determinants of 5-year weight gain in midage women. Obes Res 2005;13:1431–1441. Burton-Freeman B, Davis PA, Schneeman BO. Interaction of fat availability and sex on postprandial satiety and cholecystokinin after mixed-food meals. Am J Clin Nutr 2004;80:1207–1214. Burton-Freman B, Davis PA, Schneeman BO. Plasma cholecystokinin is associated with subjective measures of satiety in women. Am J Clin Nutr 2002;76:659–667. Cox JE, Kelm GR, Meller ST, Randich A. Suppression of food intake by GI fatty acid infusions: roles of celiac vagal afferents and cholecystokinin. Physiol Behav 2004;82:27–33. de Graaf C, Blom WA, Smeets PA, Stafleu A, Hendriks HF. Biomarkers of satiation and satiety. Am J Clin Nutr 2004;79:946–961. Degen L, Matzinger D, Drewe J, Beglinger C. The effect of cholecystokinin in controlling appetite and food intake in humans. Peptides 2001;22:1265–1269. Drewe J, Gadient A, Rovati LC, Beglinger C. Role of circulating cholecystokinin in control of fat-induced inhibition of food intake in humans. Gastroenterology 1992;102:1654–1659. Feinle C, Rades T, Otto B, Freid M. Fat digestion modulates gastrointestinal sensations induced by gastric distension and duodenal lipids in humans. Gastroenterology 2001;120:1100–1107. Feltrin KL, Little TJ, Meyer JH, Horowtiz M, Smout AJPM, Wishart J, Pilichiewicz AN, Rades T, Chapman IM, Fienle-Bisset C. Effects of intraduodenal fatty acids on appetite, antopyloroduodenal motility, and plasma CCK and GLP-1 in humans vary with their chain length. Am J Physiol 2004;287:R524–R533. Flint A, Raben A, Astrup A, Holst J. Glucagon like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515–520. Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord 2000;24: 38–48.


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Flint A, Raben A, Ersbø´ ll AK, Holst JJ, Astrup AA. The effect of physiological levels of glucagon like peptide 1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes 2001;25:781–792. Frost GS, Brynes AE, Dhillo WS, Bloom SR, McBurney MI. The effects of fibre enrichment of pasta and fat content on gastric emptying, GLP-1, glucose, and insulin responses to a meal. Eur J Clin Nutr 2003;57:293–298. Geary N, Kissileff HR, Pi-Sunyer FX, Hinton V. Individual, but not simultaneous, glucagon and cholecystokinin infusions inhibit feeding in men. Am J Physiol 1992;262:R975–R980. Greenman Y, Golani N, Gilad S, Yaron M, Limor R, Stern N. Ghrelin secretion is modulated in a nutrient- and gender-specific manner. Clin Endocrinol 2004;60:382–388. Greenough A, Cole G, Lewis J, Lockton A, Blundell JE. Untangling the effects of hunger, anxiety and nausea on food intake during intravenous cholecystokinin octapeptide (CCK-8) infusions. Physiol Behav 1998;65:303–310. Guimbaud R, Moreau JA, Bouisson M, Durand S, Escourrou J, Vaysse N, Frexinos J. Intraduodenal free fatty acids rather than triglycerides are responsible for the release of CCK in humans. Pancreas 1997;14:76– 82. Gutzwiller J-P, Degen L, Matzinger D, Prestin S, Beglinger C. Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men. Am J Physiol Regul Integr Comp Physiol 2004;287:R562–R567. Gutzwiller J-P, Drewe J, Goke B, Schmidt H, Rohrer B, Lareide J, Beglinger C. Glucagon like peptide promotes satiety and reduced food intake in patients with diabetes mellitus. Am J Physiol 1999a;276: R1541–R1545. Gutzwiller J-P, Drewe J, Ketterer S, Hildebrand AK, Beglinger C. Interaction between CCK and a preload on reduction of food intake is mediated by CCK-A receptors in humans. Am J Physiol 2000;279:R189–R195. Gutzwiller J-P, Goke B, Drewe J, Hildebrand P, Ketterer S, Handschin D, Winterhalder R, Conen D, Beldlinger C. Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut 1999b;44:81–86.


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Halford JCG. What’s new in the appetite suppressant field. A nutritional and behavioural perspective. Agro Foods Industry Hi-Tech. Anno 18—No. 5 September/October 2007. Halton TI, Hu FB. The effects of high protein diets on thermogenesis, satiety and weight loss. A critical review. J Am Coll Nutr 2005;23:373–385. Hildebrand P, Petrig C, Buckhardt B, Ketterer S, Lengsfeld H, Fleury A, Hadvary P, Belinger C. Hydrolysis of dietary fat by pancreatic lipase stimulated cholecystokinin releases. Gastroenterology 1998;114:123–129. Hopman WPM, Jansen JB, Lamers CB. Comparative study of the effects of equal amounts of fat, protein, and starch on plasma cholecystokinin in man. Scand J Gastroenterol 1985;20:8437. Hughes GM, Boyland EJ, Williams NJ, Mennen L, Scott C, Kirkham TC, Harrold JA, Keizer HG, Halford JC. The effect of Korean pine nut oil (PinnoThin) on food intake, feeding behaviour and appetite: a double-blind placebo-controlled trial. Lipids Health Dis 2008;7:6. Kissileff HR, Pi-Sunyer X, Thornton J, Smith GP. C-terminal octapeptide of cholecystokinin decreases food intake in man. Am J Clin Nutr 1981;34:154–160. Kong M-F, Chapman I, Goble A, Wishart J, Wittert G, Morris H, Horowitz M. Effects of oral fructose and glucose on plasma GLP-1 and appetite in normal subjects. Peptides 1999;20:545–551. Lavin JH, Wittert GA, Andrews J, Yeap B, Wishart JM, Morris HA, Morley JE, Horowitz M, Read NW. Interaction of insulin, glucagonlike peptide 1, gastric inhibitory polypeptide, and appetite in response to intraduodenal carbohydrate. Am J Clin Nutr 1998;68: 591–598. Lawton CL, Delargy HJ, Brockman J, Smith FC, Blundell JE. The degree of saturation of fatty acids influences post-ingestive satiety. Br J Nutr 2000;83:473–482. Lieverse RJ, Jansen JBMJ, Masclee AAM, Rovati LC, Lamers CBHW. Effect of a low dose of intraduodenal fat on satiety in humans: studies using the type A cholecystokinin receptor antagonist loxiglumide. Gut 1994;35:501–505. Little TJ, Russo A, Meyer JH, Horowitz M, Smyth DR, Bellon M, Wishart JM, Jones KL, Feinle-Bisset C. Free fatty acids have more potent effects


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on gastric emptying, gut hormones, and appetite than triacylglycerides. Gastroenterology 2007;133(4):1124–1131. Näslund E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ, Rössner S, Hellström PM. Energy intake and appetite are suppressed by glucagon like peptide 1 (GLP-1) in obese men. Int J Obes 1999;23:304–311. Näslund E, Gutniak M, Skogar S, Rössner S, Hellström PM. Glucagon-like peptide 1 increase the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr 1998;68:525–530. Pasman WJ, Heimerikx J, Rubingh CM, Van Den Berg R, O’Shea M, Gambelli L, Hendriks HF, Einerhand AW, Scott C, Keizer HG, Mennen LI. The effect of Korean pine nut oil on in vitro CCK release, on appetite sensations and on gut hormones in post-menopausal overweight women. Lipids Health Dis 2008;7:10. Poppitt SD, Leahy FE, Keogh GF, Wang Y, Mulvey TB, Stojkovic M, Chan YK, Choong YS, McArdle BH, Cooper GJ. Effect of high-fat meals and fatty acid saturation on postprandial levels of the hormones ghrelin and leptin in healthy men. Eur J Clin Nutr 2006;60:77–84. Ranganath LR, Beety JM, Morgan LM, Wright W, Howland R, Marks V. Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 1996;38:916–919. Slavin JL. Dietary fibre and body weight. Nutrition 2005;21:411–418. Stubbs RJ, Hughes DA, Johnstone AM, Rowley E, Reid C, Elia M, Stratton R, Delargy H, King N, Blundell JE. The use of visual analogue scales to assess motivation to eat in human subjects: a review of their reliability and validity with an evaluation of new hand-held computerized systems for temporal tracking of appetite ratings. Br J Nutr 2000;84: 405–415. Thomsen C, Rasmussen O, Losen T, Holst JJ, Fenselau S, Schrezenmeir J, Hermansen K. Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects. Am J Clin Nutr 1999;69:1135–1143. Thomsen C, Storm H, Holst JJ, Hermansen K. Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagonlike peptide 1 responses in patients with type 2 diabetes. Am J Clin Nutr 2003;77:605–611.


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Verdich C, Flint A, Gutzwiller JP, Naslund E, Beglinger C, Hellstrom PM, Long SJ, Morgan LM, Holst JJ, Astrup A. A meta-analysis of the effect of glucagon-like peptide-1 (7–36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab 2001;86:4382–4389. Wolff RL, Pédrono F, Pasquier E, Marpeau AM. General characteristics of Pinus spp. seed fatty acid compositions, and importance of delta5olefinic acids in the taxonomy and phylogeny of the genus. Lipids 2000;35(1):1–22. Wynne K, Stanley S, McGowan B, Bloom S. Appetite control. J Endocrinol 2005;184:291–318.


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CHAPTER 3

Sucrose Fatty Acid Ester (Olestra) John C. Peters, PhD

Abstract Despite 20 years of mounting evidence concerning the implications of eating too much fat, people still consume more than the recommended amount. While nutrition experts agree that the optimal method for reducing fat in the diet is to replace high-fat foods with low-fat choices, the reality is that most people find it difficult to eliminate foods containing fat from their everyday meals and snacks. For more than 30 years, scientists and researchers at The Procter & Gamble Company have been working with a fat substitute known as olestra (brand name Olean). Although olestra looks, cooks, and tastes like conventional fat, it is not broken down by the body. In 1996, FDA approved olestra as a replacement for up to 100% of the conventional fat in savory snacks. Because the olestra molecule can be manipulated for application in a wide variety of food formulations, it is an ideal choice for eliminating all fat, and thus all calories from fat, in some foods or for blending with dietary fat for reducing calorie content. In addition to its potential impact on weight control, olestra has been shown to have a positive impact on cardiovascular and metabolic risk factors and may also provide a therapeutic approach for reducing levels of fat-soluble environmental contaminants in the body such as dioxin. Reduce total fat intake to 30% or less of calories. Reduce saturated fatty acid intake to less than 10% of calories and the intake of cholesterol to less than 300 mg daily. The intake of fat and cholesterol can be reduced by substituting fish, poultry without skin, lean meats, and low- or nonfat dairy products for fatty meats and whole-milk dairy products; by choosing 43


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more vegetables, fruits, cereals, and legumes; and by limiting oils, fats, egg yolks, and fried and other fatty foods. Diet and Health: Implications for Reducing Chronic Disease Risk Committee on Diet and Health, National Research Council National Academies Press, 1989

Since the United States National Research Council issued its 1989 landmark report, Diet and Health: Implications for Reducing Chronic Disease Risk, dietary fat has been a primary focus among nutrition and health professionals worldwide, and consumers have struggled to follow the council’s now ubiquitous “30% of calories” recommendation for fat intake. In its earliest incarnation, consumer interest in low-fat eating was driven primarily by the link between dietary fat and cardiovascular disease. Over time, as research showed that not all dietary fat is “bad for the heart,” consumer focus shifted to the impact of dietary fat on weight, and the spotlight shifted from fat as a risk factor for clogged arteries to fat as a risk factor for eating too many calories. Despite 20 years of mounting evidence concerning the implications of eating too much fat, however, people still consume more than the recommended amount. Although the percentage of calories from total fat decreased from 36.9% to 32.8% for men and from 36.1% to 32.8% for women between 1971–1974 and 1999–2000, Americans are still consuming more than their healthy share of fat. In fact, the decrease in percentage of calories from fat is attributed to an increase in total calories consumed; absolute fat intake in grams has actually increased (Table 3.1). Making any dietary change is a complex process. Research shows that reducing fat in the diet is one of the most difficult behaviors to sustain (American Dietetic Association, 2006; Drewnowski and Rolls, 2005). While nutrition experts agree that the optimal method for reducing fat in the diet is to replace high-fat foods with low-fat choices such as whole grains, fruits, and vegetables, the reality is that most people find it impossible—and undesirable—to eliminate foods containing fat from their everyday meals and snacks. Table 3.1. Mean energy intake among adults and percentage of calories from fat among adults during 1971–2000 Men

Women

Time Frame

Kilocalories per Day

Percentage of Kilocalories from Fat

Kilocalories per Day

Percentage of Kilocalories from Fat

1971–1974 1976–1980 1988–1994 1999–2000

2,450 2,439 2,666 2,618

36.9 36.8 33.9 32.8

1,542 1,522 1,798 1,877

36.1 36.0 33.4 32.8

Source: Wright et al., 2004.


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Sucrose Fatty Acid Ester (Olestra)

45

Although overconsumption of particular fatty acid compositions has known health risks, fat is also vital to human growth and development and key to certain physiological processes. In addition, fat imparts important functional and sensory qualities to food, including flavor, softness, chewiness, smoothness, and creaminess. Fat helps maintain moisture in food, influences food stability for storage, creates structure in baked goods, and helps transmit the heat that creates crsipiness. Fat also carries, enhances, and release flavor. Because fat performs so many diverse and complex functions in food, it is difficult to eliminate or replace it in whole foods and in food formulations without affecting function and consumers’ number one criterion for food choice, taste. Almost two decades ago, the U.S. Department of Agriculture challenged food manufacturers to develop at least 5,000 reduced-fat products by the year 2000. This goal was easily met and surpassed by 1995 (International Food Information Council, 2000). What these early products lacked in fat, however, they often made up for in added salt and sugar in an effort to preserve flavor. Nevertheless, taste and texture remained an issue for consumers. Taste continues to rule consumer food choice today, but as the quest for overall wellness and the desire for healthful food become mainstream, the demand for flavorful reduced-fat foods that can be seamlessly incorporated into everyday eating is increasing rapidly.

The Evolution of Olestra For more than 30 years, scientists and researchers at The Procter & Gamble Company (P&G), a multinational consumer products company based in Cincinnati, Ohio, have been working with a fat substitute known as olestra (brand name Olean). P&G chemists created olestra, a sucrose polyester, through a multistep process that combines two naturally occurring substances, sucrose and vegetable oil (soybean or cottonseed). The result is a proprietary cooking oil/shortening that adds no fat, no calories, no transfat, and no cholesterol to food yet maintains the properties of normal fat flavor, texture, mouthfeel, and thermal stability. Although olestra looks, cooks, and tastes like conventional fat, it is not broken down by the body. While the typical fat molecule is composed of three fatty acid chains attached to a glycerol core, the olestra molecule is composed of six to eight fatty acid chains attached to sucrose core. Like the insoluble fiber in apples, corn, and bran, olestra is impossible for gastrointestinal enzymes to digest (Fig. 3.1). Because other fat replacers mimic only one or two functions of fat, they must be mixed and matched into “systems” in order to replace conventional fat in foods. Olestra, however, is a fat; therefore, it does not have to be combined with other replacers in order to be effective. Olestra can be made


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Figure 3.1. Olestra molecule.

from fatty acids derived from different types of vegetable oil and can be tailored to replace conventional fat in various foods. In the early 1970s, P&G began meeting with the U.S. Food and Drug Administration (FDA) to discuss using olestra in foods. Because olestra is a novel food ingredient, it required FDA approval as a food additive. In 1987, P&G filed a petition with the FDA. The agency’s 22-member Food Advisory Committee subsequently reviewed approximately 100 animal and 40 human studies, including more than 40 tightly controlled clinical studies in more than 5,000 men, women, and children, plus an additional 55 sensory or preference studies in more than 20,000 people. (See www.olean.com/default.asp?p=prof&id=sc for a guide to olestra studies.) With the depth and breadth of this scrutiny—which covered areas such as nutritional and gastrointestinal effects, weight management, drug interactions, toxicology biomarkers for cancer, heart disease, and allergic reaction—olestra became one of the most studied food ingredients of all time. In 1996, FDA approved olestra as a replacement for up to 100% of the conventional fat in savory snacks such as potato chips, tortilla chips, cheese puffs, and crackers. Because olestra holds up under the high temperature of frying, it imparts the same taste and texture as conventional frying oil—a benefit other fat replacers cannot claim. Some nutrition experts questioned why P&G chose to “make a bad food good” by replacing the fat in a snack such as potato chips. The answer


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rests in the simple reality of consumer behavior: Despite the high amount of unhealthy dietary fat in potato chips, people enjoy them, eat a lot of them, and are loathe to give them up no matter what health authorities recommend. Thus, potato chips are a good target for reducing fat and calories in the American diet. In granting P&G’s petition, FDA required that products containing olestra carry a label informing consumers that after eating olestracontaining snacks, some people may experience temporary digestive effects, and that vitamins A, D, E, and K have been added to the product to compensate for the possibility that in the presence of olestra, not all of the fat-soluble vitamins present in the food would be absorbed. In 2003, FDA authorized removal of this information label, and in the following year, FDA approved olestra for use in microwave popcorn. In 2007, P&G submitted a GRAS notification to FDA that provided data supporting olestra’s use in prepackaged ready-to-eat cookies.

The Role of Olestra in Weight Prevention, Loss, and Maintenance Health experts around the world agree that obesity has become a serious global issue. High blood pressure, heart attack and stroke, type 2 diabetes, gallbladder disease, and certain cancers have been linked directly to obesity (American Dietetic Association, 2006; Drewnowski and Rolls, 2005). Research indicates that the path to obesity is paved with foods high in fat. Not only are high-fat foods energy dense, but calorie for calorie, dietary fat is thought to be less satiating than protein or carbohydrate and thus promotes overeating. In addition, excess dietary fat is more easily stored as body fat (Bray et al., 2002; Hill, 2006; Peters, 2003). Consuming foods in which some of all of the dietary fat has been replaced is one way to help reduce the amount of fat and hence the number of calories consumed. To fully appreciate the potential impact of reduced-fat food on weight prevention, loss, and maintenance, it is necessary to understand three core concepts: volume/weight versus calories consumed, energy density, and compensation. Research by Barbara Rolls and others has shown that over the course of several days, people tend to eat a consistent weight/volume of food rather than a certain number of calories (Rolls et al., 2005). Theoretically, if the weight of food eaten remains the same over time, but the calories in that volume food are reduced, the appetite should be satisfied with fewer


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calories. Typically, the body does not notice differences in calorie intake unless it is losing weight, in which case it will trigger a primitive defensive mechanism to prevent the threat of perceived starvation. The number of calories (amount of energy) in a given volume of food such as a cubic centimeter is called energy density. Practically speaking, on a label, this concept is expressed as calories per gram. When a food is low in energy density, more of that food can be consumed without contributing calories to the diet. At one end of the spectrum of food components, water (including the water intrinsic in fruits and vegetables) has the most impact on energy density because it adds weight (volume) without adding calories. At the other end of the spectrum, fat has the greatest impact on energy density because among the macronutrients, fat adds the most calories per unit of volume—9 kcal/g versus only 4 kcal/g for carbohydrate and protein. Rolls and others have also demonstrated that when the energy density of a given weight of food is lowered, even by as much as 30%, individuals do not notice the decrease and report levels of hunger and satiety (fullness) similar to what they experience in their normal diet—because they have consumed the same weight/volume of food as usual. Thus, it is not surprising that higher energy density diets are associated with higher energy (calorie) intakes and that energy density has a stronger impact on energy intake than does any one macronutrient (Rolls et al., 2005). Because lower fat diets generally have a lower energy density, however, fat reduction can be an effective strategy for reducing calorie intake as long as fat calories are exchanged for foods that are naturally low in energy density—fruits, vegetables, and whole grains—or for foods that contain an ingredient such as olestra that has been modified to deliver all the taste and texture benefits of natural fat without the calories. For example, on average, every person in America eats 21 pounds of salted snacks per year. Those snacks contain nearly 6 pounds—more than 22,800 calories—of fat. As a nation, Americans eat more than 5.6 billion pounds of salted snacks per year. In these snacks, they consume about 774,000 tons of fat, or more than 6 trillion calories. If only 10% of these people ate snacks made with olestra instead of full-fat snacks, Americans would avoid 77,400 tons of fat and more than 600 billion calories in a single year. A 1-ounce serving of potato chips fried with olestra contains only 70 calories and 0 g of fat versus 150 calories and 10 g of fat in regular chips (Table 3.2). Since olestra has been available, consumers have purchased more than 5 billion servings of olestra products, saving more than 130 million pounds of body fat.


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Table 3.2. The impact of olestra Full Fat Potato Chips (28 g) Fat/serving kcal/serving Tortilla Chips (28 g) Fat/serving kcal/serving Cheese Curls (28 g) Fat/serving kcal/serving

100% Olestra

10 g 150 8g 150

0g 70

% Reduction 100 55

1 g from corn 90

85 40

>1 70

85 45

10 160

Source: The Procter & Gamble Company.

Dieting versus “Lifestyling” Although numerous diets are available to help people lose weight in the short term, successful weight-loss maintenance and the prevention of the weight gain associated with aging require a permanent change in lifestyle. For example, dietary fat reduction is a popular weight-loss strategy, but long-term compliance with any diet that restricts food is too challenging for most people. As James Hill and others have demonstrated, food restriction is not only contrary to human biology but also creates counterproductive metabolic changes (Hill, 2006). According to data from the 5,000-plus-member National Weight Control Registry (www.nwcr.ws), however, incorporating fat-modified foods into the diet is a strategy frequently used by people who are successful with weight maintenance. Not all mimetics and substitutes used to replace dietary fat can withstand the high heat of frying or baking and not all are as flavorful as natural fat. In addition, some fat replacers still contain calories—sometimes more than the number of calories found in carbohydrate and protein. Olestra, however, can be used at high temperature, mimics the taste and texture of “real” fat, and adds no calories. Human studies reviewed in a 2001 issue of Critical Reviews in Food Science and Nutrition and in a 2002 issue of Obesity Reviews have shown the short-term and long-term effects of a sucrose polyester such as olestra on energy intake and satiety in adults and children (Eldridge et al., 2002; Stubbs, 2001). For example: r When olestra was used to reduce fat from approximately 40% of

energy to 30% of energy over a 10-week period, the body did not metabolically detect the lost fat. Study subjects using olestra barely


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compensated for the lost energy. Subjects consuming a traditional reduced-fat diet, however, experienced greater energy compensation (Roy et al., 2002). r In a 9-month randomized clinical trial of healthy obese men, a diet in which olestra was substituted for one-third of dietary fat (resulting in a diet with 33% total fat, but only 25% metabolizable fat) was compared with diet having 33% and 25% calories from fat without olestra. Subjects on the olestra diet lost more weight and more body fat than did those in the other two groups (Bray et al., 2002; Lovejoy et al., 2003). These studies suggest an important role for olestra in allowing people to have access to good-tasting foods that normally would be restricted on a weight-loss diet and thus improving short- and long-term diet compliance.

Olestra’s Potential Food Applications Olestra can be used to modify the energy density of food wherever intrinsic fat is present. Removing just 1–2 g of fat from the typical diet each day would prevent the 1- to 2-pound annual weight gain experienced by the average adult (Hill, 2006; Hill et al., 2003). Because the olestra molecule can be manipulated for application in a wide variety of food formulations, it is an ideal choice for eliminating all fat, and thus all calories from fat, in some foods or for blending with dietary fat for reducing calorie content. When P&G first introduced olestra, its use in savory snacks such as chips and then microwave popcorn was aimed at eliminating fat from indulgent foods, thus making it easier for people to enjoy these items and still cut down on calories. As olestra technology has progressed, P&G scientists have been successful in lowering fat calories while preserving taste and texture by using olestra oil, shortening, and fat blends in a wide variety of products (Table 3.3).

Other Health Considerations In addition to its potential impact on weight prevention, loss, and maintenance, olestra has been shown to have a positive impact on cardiovascular and metabolic risk factors such as cholesterol level, blood pressure, and fasting insulin. In one study, “consumption of a low-fat diet containing olestra for 9 months produced significant improvement in cardiovascular risk factors” such as the reduction LDL (bad) cholesterol and triglyceride


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Table 3.3. Olestra fat/oil replacement formulation matrix Applications Capable Today Baked Goods Dough Cookies Cakes Pie crusts Biscuits Frying Chips French fries Doughnuts Fried meats/fish Other Confectionary coatings Popcorn

Olestra Oil

Olestra Blends

Olestra Shortening

X

X X X X

X X X X X

X X X X

X X X X

X

Formulations: Fast Development Dairy Ice cream Processed cheese Cheddar Mozzarella Cream cheese Spreads Mayonnaise X Peanut butter Margarines X Other Fillings/icings Confections/candy Prepackaged direct fat substitute X Formulations: More Development Needed Dairy Custard/pudding Cottage cheese Milk Yogurt Cream Other Sauces/gravies Meats/sausage Source: The Procter & Gamble Company.

X X X X X

X

X X X

X X X X X TBD TBD

X


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levels, and increased HDL (good) cholesterol. The researchers attribute these results to weight loss, which occurred because the study subjects using olestra were able to adhere to their low-fat diets for 9 months (Patterson et al., 2000; Roy et al., 2002). In another study, researchers demonstrated that just a single meal containing olestra can have a positive effect on the resiliency of blood vessels (Cook et al., 2000). Olestra also may provide a therapeutic approach for reducing levels of fat-soluble environmental contaminants in the body such as dioxin (Geusau et al., 1999; Moser and McLachlan, 1999). In addition, olestra may assist in ridding the body of fat-soluble organochlorines released into the blood stream by adipose tissue during weight loss. Organochlorines, which are found in substances such as lubricants and coolants for electrical appliances and in insecticides such as DDT, resist degradation and are stored in fat cells. They have been associated with cancer as well as immune system and thyroid disorders (Pelletier et al., 2003).

References American Dietetic Association. Position of the American Dietetic Association: fat replacers. J Am Diet Assoc 2006;106(2):266–275. Bray GA, Lovejoy JC, Most-Windhauser M, Smith, SR, Volaufova J, Denkins Y, de Jonge L, Rood J, Lefevre M, Eldridge AL, Peters JC. A 9-mo randomized clinical trial comparing fat-substituted and fatreduced diets in healthy obese men: the Ole Study. Am J Clin Nutr 2002;76: 928–934. Cook B, Cooper D, Fitzpatrick D, Smith, S, Tierney D. The influence of a high fat meal compared to an olestra meal on coronary artery endothelial dysfunction by rubidium (RB)-82 positron emission tomography (PET) and on post prandial serum triglycerides. Clin Positron Imaging 2000;4:150. Research chosen for presentation to the media at the 12th Annual International PET Conference, October 18, 2000, Washington, DC. Drewnowski A, Rolls BJ. How to modify the food environment. J Nutr 2005;135:898–899. Eldridge AL, Cooper DA, Peters JC. A role for olestra in body weight management. Obesity Rev 2002;3:17–25.


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Geusau A, Tschachler E, Meixner M, Sandermann S, Papke O, Wolf C, Valic E, Stingl G, McLachlan M. Olestra increases faecal excretion of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Lancet 1999;354(9186):1255– 1267. Hill JO. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocrine Rev 2006;27:750–761. Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go from here? Science 2003;299:853–855. International Food Information Council. IFIC review: uses and nutritional impact of fat reduction ingredients. 2000. Available online at www.ific.org/publications/reviews/upload/Uses-Nutritional-Impactof-Fat-Reduction-Ingredients.pdf. Lovejoy JC, Bray GA, Lefevre M, Smith SR, Most MM, Denkins YM, Volaufova1 J, Rood JC, Eldridge, AL, Peters JC. Consumption of a controlled low-fat diet containing olestra for 9 months improves health risk factors in conjunction with weight loss in obese men: the Ole Study. Int J Obesity 2003;27:1242–1249. Moser GA, McLachlan MS. A non-absorbable dietary fat substitute enhances elimination of persistent lipophilic contaminants in humans. Chemosphere 1999;39(9):1513–1521. Patterson RE, Kristal AR, Peters JC, Neuhouser ML, Rock CL, Cheskin LJ, Neumark-Sztainer D, Thornquist MD. Changes in diet, weight, and serum lipid levels associated with olestra consumption. Arch Intern Med 2000;160:2600–2604. Pelletier C, Imbeault P, Tremblay A. Energy balance and pollution by organochlorines and polychlorinated biphenyls. Obes Rev 2003;4(1):17–24. Peters JC. Dietary fat and body weight control. Lipids 2003;38:123–127. Rolls BJ, Drewnowsk A, Ledikwe JH. Changing the energy density of the diet as a strategy for weight management. J Am Diet Assoc 2005;105:S98–S103. Roy HJ, Most MM, Sparti A, Lovejoy JC, Volaufova J, Peters JC, Bray GA. Effect on body weight of replacing dietary fat with olestra for two or ten weeks in healthy men and women. J Am Coll Nutri 2002;21(3):259– 267.


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Stubbs RJ. The effect of ingesting olestra-based foods on feeding behavior and energy balance in humans. Crit Rev Food Sci Nutr 2001;41(5):383–386. Available online at http://dx.doi.org/10.1080/ 20014091091850. Wright JD, Kennedy-Stephenso J, Wang CY, McDowell MA, Johnson CL. Trends in intake of energy and macronutrients—United States, 1971–2000. Morb Mortal Wkly Rep 2004;53(4):80–82.


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CHAPTER 4

The Effects of a Novel Fat R / Emulsion (Olibra FabulessTM) on Energy Intake, Satiety, Weight Loss, and Weight Maintenance Rick Hursel, MSc, and Prof. Dr. Margriet Westerterp-Plantenga, PhD

Abstract As obesity is becoming a major problem in the developed countries, scir / ence tries to find strategies for weight loss and weight maintenance. Olibra TM Fabuless is an example of such a strategy. This fat emulsion can replace milk fat, and through its physicochemical properties, it may increase satiety. Shortr /FabulessTM has a suppressive effect on the term studies have shown that Olibra appetite ratings and that it enhances satiety. Only the studies from Burns et al. reported an actual lowering effect on energy intake. They also showed that there is a r /FabulessTM on energy intake. No effect was seen dose-response effect of Olibra considering energy intake on the long term, but the fat emulsion did contribute to weight maintenance in a long-term study by Diepvens et al., due to decreased r /FabulessTM has been feelings of hunger. The observed satiating effect of Olibra suggested to be the result of the ileal brake mechanism. This ileal brake initiates a feedback loop that inhibits upper gut motility (to slow gastric emptying and 55


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intestinal transit) in response to nutrients in the distal small intestine, which cause r /FabulessTM components are entirely natural and no satiety signals. The Olibra study recorded any side effects.

Introduction The prevalence of obesity has increased worldwide during the past few decades (Seidell, 1998). Obesity is a major causative factor for a number of diseases, including coronary heart disease, hypertension, noninsulindependent diabetes mellitus, pulmonary dysfunction, and certain types of cancer (Stunkard, 1996). Obesity develops when the equilibrium between energy intake (EI) and energy expenditure (EE) shifts toward a positive energy balance. Treatment of obesity is beneficial in that weight loss reduces the risk for mortality and morbidity. Even modest weight loss, such as 5–10% of the initial body weight, has beneficial health effects (Goldstein, 1992). Body weight loss and prevention of body weight (re)gain can be achieved by reducing EI and/or increasing EE, or promoting fat oxidation. r is a novel fat emulsion consisting of a mixture of fractionated Olibra palm oil (40%) and fractionated oat oil (2.5%) in water. The emulsion r corresponds to can be incorporated into yogurts, whereby 5 g of Olibra about 2 g of milk fat, the common fat in yogurts (Diepvens et al., 2007). r , may have Fats with different physicochemical properties, such as Olibra different effects on satiety (Burns et al., 2000). r is an example of an active ingredient that aims to promote Olibra reduction of EI by promoting and maintaining satiety. R Efficacy of Olibra

Short-Term Experiments Burns et al. were the first to report the effects of a novel fat emulsion, also r . In their initial study, they investigated the short-term known as Olibra r on the dietary intakes of nonobese subjects, especially effects of Olibra energy and macronutrient intakes (Burns et al., 2000). Subjects received either yogurt with the novel fat emulsion or yogurt that contained normal dairy fat. Results showed that EI was significantly decreased (13.9% reduction in EI, p > 0.001; EI: 6.67 ± 2.1 MJ after test yogurt compared to 7.75 ± 1.8 MJ after placebo yogurt) at a meal, 4 hours postconsumption of r compared to the control yogurt. Fat (18.9%), carthe yogurt with Olibra bohydrate (10.1%), and protein (12.1%) intake were significantly reduced


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The Effects of a Novel Fat Emulsion


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after the test yogurt compared to the placebo yogurt, with the strongest reduction in fat intake. Subjects also ate a smaller amount of food after the intervention with the novel fat emulsion (Burns et al., 2000). These results indicate that subjects were more satiated 4 hours postconsumption of the test yogurt compared to the control yogurt. Appetite was rated with visual analogue scales (VASs, in mm). Subjects reported that they felt r containing yogurt and that they ate less more satiated after the Olibra for the remainder of the day (till 21:00 hour) following the control yogurt (Burns et al., 2000). Whether these obtained results are also applicable in obese subjects remained unknown from this study. It was expected that obese subjects would respond differently because they have an increased preference for high-fat foods, although these foods are less satiating in obese subjects (Lawton et al., 1993). In a subsequent study, Burns et al. conducted a study that was comparable to the first one. In addition to the nonobese subjects participating in the previous study, they also included overweight and obese subjects. They extended the observation of the subjects from 4 to 8 hours postconsumption. It was shown that, in comparison with a yogurt containing normal r significantly milk fat, consumption of a 200-g yogurt containing Olibra decreased EI in normal weight and overweight subjects, at a meal 4 and 8 hours later, and in obese subjects 8 hours postconsumption, and that the decreased intake persisted for the rest of the day (Burns et al., 2001). However, the magnitude of the responses observed 4 hours postconsumption were not as significant in the overweight (27.6% reduction in EI, p < 0.05; EI: 4.43 ± 0.38 MJ after test yogurt compared to 6.12 ± 0.47 MJ after placebo yogurt) and obese group (13.1% reduction in EI, ns; EI: 4.56 ± 0.41 MJ after test yogurt compared to 5.25 ± 0.44 MJ after placebo yogurt) compared to the nonoverweight group (30.2% reduction in EI, p < 0.05; EI: 3.82 ± 0.29 MJ after test yogurt compared to 5.38 ± 0.34 MJ after placebo yogurt). Furthermore, despite reduced subsequent EI, contradictory results were seen in hunger and satiety recordings (Burns et al., 2001). It was speculated by Burns et al. that the lower response of the obese r may have been caused because subjects to the yogurt containing Olibra of a lower dose (expressed relative to body weight) (Burns et al., 2001). The same research group investigated this hypothesis and they revealed that relative to the control yogurt, mean EIs (2 g: 21% reduction in EI, EI: 5.83 ± 1.91 MJ; 4 g: 25% reduction in EI, 5.60 ± 1.89 MJ; 6 g: 30% reduction in EI, 5.24 ± 1.91 MJ compared to control yogurt 7.42 ± 1.89 r in subjects MJ, p > 0.05) were reduced with an increasing dose of Olibra with normal weight and overweight (Burns et al., 2002). A larger effect after the test yogurt was seen in females in contrast to males, which can


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be explained by higher body weight in male subjects. Males received a lower dose relative to their body weight (Burns et al., 2002). There were no significant differences regarding satiety and appetite ratings between control and different dosages (Burns et al., 2002). r on appetite Diepvens et al. also studied the short-term effects of Olibra and food intake (Diepvens et al., 2008), since results, as obtained by Burns et al., had not been confirmed by other studies, thus far (Burns et al., 2000, 2001, 2002). Consequently, the aim of this study was to assess the effect r versus placebo in the short term by investigating the possible of Olibra r in junior-normal weight and senior-overweight groups, effects of Olibra on appetite ratings and EI 4 hours later, in similar groups as in the Burns studies. No difference was seen in food intake (test: 467.6 ± 114.3 g; placebo: 450.1 ± 90.7 g) between the test yogurt and the placebo yogurt, r emulsion did at lunch 4 hours postconsumption. However, the Olibra exert a suppressive effect on appetite ratings in the short term (Diepvens et al., 2008). Nevertheless, this was not sufficient to reduce EI. Less food was eaten in the junior-normal weight group compared to the senioroverweight group, which can be subscribed to the higher bodyweight of the latest. As explained before, the dosage may have been insufficient for this group. There might be a possibility that the emulsion prevents overeating, but this could not be confirmed by this study (Diepvens et al., 2008).

Long-Term Experiments After the positive effects of the short-term studies by Burns et al., it r has any long-term effects as well. was time to reveal whether Olibra r emulsion during Logan et al. investigated the effects of the Olibra r , 3 weeks. Subjects received either 200 g yogurt, containing 5 g Olibra or the control that was 5 g of milk fat. On day 1, 8, and 22, food intake 4 hours postconsumption of the yogurts was assessed (Logan et al., 2006). In contrast to some short-term studies, no long-term effects were found r containing yogurt (day 1, EI: 5.04 ± 1.54 after consuming the Olibra MJ after test yogurt compared to control yogurt EI: 5.06 ± 1.54 MJ, ns; day 8, EI: 4.92 ± 1.40 MJ after test yogurt compared to control yogurt EI: 5.22 ± 1.67 MJ, ns; day 22, EI: 5.02 ± 1.57 MJ after test yogurt compared to control yogurt EI: 5.06 ± 1.46 MJ, ns). There was neither on day 1, 8, or 22 a significant difference in mean energy, macronutrients, or amounts of food eaten 4 hours postconsumption. The appetite ratings also failed to result in any significant effects (Logan et al., 2006).


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Logan et al. came up with several explanations for the results of their study. The eating environment during lunch, for instance, was more sociable compared to the results of previous studies, which can influence food intake. People tend to overeat when the ambience is more sociable (Stroebele and De Castro, 2004). Another reason may be the period in which the study was conducted, August and November. People are more prone to overeat during autumn and winter compared to summer and spring (Shahar et al., 2001). In another long-term study, Diepvens et al. assessed a possible weight r maintenance (after a very low energy diet) by consumption of Olibra up till 18 weeks. Hunger ratings, satiety-related hormones, resting energy expenditure (REE), and body composition were assessed as well (Diepvens et al., 2007). After the weight-loss period, the subjects in the r containing yogurt, showed no significant test group, who ate the Olibra increase in weight (1.2 kg (15.5%) regain, ns) in contrast with the subjects who ate the control yogurt (3.0 kg (40.3%) regain, p > 0.05) (Figs. 4.1 and 4.2) Glugacon-like peptide-1 (GLP-1) values were significantly increased at 180 minutes postconsumption of the test yogurt at week 25 compared to week 1. In week 25, a significant difference was found between both groups, in that the test group was less hungry 4 hours after the yogurt compared with the placebo group (Diepvens et al., 2007). REE

84

Olibra Placebo

82

Body weight (kg)

80 78 76 74 *

72 70 68 8

2

26

Week

Figure 4.1. During weight maintenance, there was significant body weight r regain in the placebo group (p < 0.001), but not in Olibra group. * indicates p < 0.001 regain (kg) in placebo group (ANOVA repeated measures). (After Diepvens et al., 2007.)


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Lipid based ingredients 60

Percentage of weight regain

p=0.05 50 40 30 20 10 0 Olibra

Placebo

r Figure 4.2. Regain as percentage of weight loss was lower with Olibra as compared to placebo yogurt. Two-factor ANOVA repeated measures. (After Diepvens et al., 2007.)

was significantly increased in the test group in week 25 compared to week 7, but the same occurred in the placebo group as well. The increased REE in both groups might be a consequence of the increase in fat-free mass (FFM), as FFM is the main determinant of REE. For this reason, REE was corrected for FFM and results showed that the increase in REE could not r . fully be attributed to the increase in FFM, but also to the effect of Olibra After the correction, where REE was expressed as a function of FFM, REE was significantly increased in the test group and not in the placebo group. An FFM sparing effect occurred that prevented a lowered REE as fat mass (FM) decreased more in the test group compared to the placebo group, which was also shown by a decreased weight circumference in the test group (Diepvens et al., 2007). Eventually, this group did not regain as much weight as the placebo group, after the period of weight loss, due to a decreased feeling of hunger and an increase in REE. Another explanation r might be that participants in for the weight-maintenance effect of Olibra the weight-maintenance study had to eat the yogurt twice a day instead of once, as in the other long-term study where the effect on EI was assessed r was higher here, (Diepvens et al., 2007). The dose of consumed Olibra which had been proven to be of influence by Burns et al. (Burns et al., 2002).


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Mechanisms of Action r The observed effect of Olibra has been suggested to be the result of the ileal brake mechanism (Burns et al., 2000, 2001, 2002). This ileal brake, for which fat is the most important trigger, initiates a feedback loop that inhibits upper gut motility (to slow gastric emptying and intestinal transit) in response to nutrients in the distal small intestine (Maljaars r to increase satiety can be attributed to et al., 2007). The ability of Olibra the physicochemical properties of the emulsion. The palm oil core of the relatively small emulsion particles is covered by hydrophilic galactolipids derived from the fractionated oat oil. Due to this particular combination of triglyceride oils, resulting in delayed digestion compared to the milk fat particles, (partly) undigested particles may penetrate more distal parts of the small intestine, where sensors will detect unabsorbed fat and send satiety signals (e.g., GLP-1, CCK, PYY) to the brain. This delayed gastric emptying may evoke an indirect satiety effect (Welch et al., 1985, 1988) whereby possible inhibition of food intake is not preceded by differences in appetite ratings. However, a direct satiating effect of ileal fat perfusion without a preceding meal (Maljaars et al., 2007) was also observed; so the appetite pattern after consumption of the palm oil and fractionated oat oil may not be completely predictive for EI thereafter.

Safety The FabulessTM components are entirely natural and no study recorded any side effects. Burns et al. measured the adverse effects and gastrointestinal complaints in their subjects. They reported that the subjects did not experience any adverse effects or discomfort after the consumption of the novel fat emulsion, even not with increasing dosages (Burns et al., 2000, 2001, 2002).

Food/Supplement Applications r FabulessTM (formerly known as Olibra ) has many applications in dairy products, as the structure and composition of dairy are particularly suited to this ingredient. When administered to dairy products, the novel fat emulsion appears to enhance texture as dairy products containing FabulessTM are perceived as creamier and fuller. FabulessTM has also been launched in the form of a supplement concept. A small bottle containing the


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effective daily dose of FabulessTM offers a convenient solution for weight management, as it is supposed to reduce EI.

Patent Activities Document ID: U.S. Patent 6517883 European Patent EP0994655 Title: Satiety product Assignee: LTP Lipid Technologies Provider AB

Information on Global Suppliers After DSM (The Netherlands) gained a main interest in LTP Lipid Technologies Provider AB (Sweden), and with this the exclusive right r , they introduced the first dairy product for the production of Olibra TM with Fabuless , “ActifControl,” in Italy. Subsequently, a dairy product with FabulessTM was launched in Portugal under the brand name “Adagio Versus.” Campina launched “Optimel Control” with FabulessTM in The Netherlands. Supplements with FabulessTM are also launched in Belgium, Spain, United Kingdom (Slimthru), United States, and Turkey.

References Burns AA, Livingstone MB, Welch RW, Dunne A, Reid CA, Rowland IR. The effects of yoghurt containing a novel fat emulsion on energy and macronutrient intakes in non-overweight, overweight and obese subjects. Int J Obes Relat Metab Disord 2001;25:1487–1496. Burns AA, Livingstone MB, Welch RW, Dunne A, Robson PJ, Lindmark ´ Rowland IR. Short-term effects of yoghurt L, Reid CA, Mullaney U, containing a novel fat emulsion on energy and macronutrient intakes in non-obese subjects. Int J Obes Relat Metab Disord 2000;24:1419– 1425. Burns AA, Livingstone MB, Welch RW, Dunne A, Rowland IR. Doseresponse effects of a novel fat emulsion (Olibra) on energy and macronutrient intakes up to 36 h post-consumption. Eur J Clin Nutr 2002;56:368–377.


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Diepvens K, Soenen S, Steijns J, Arnold M, Westerterp-Plantenga M. Long-term effects of consumption of a novel fat emulsion in relation to body-weight management. Int J Obes (Lond) 2007;31:942–949. Diepvens K, Steijns J, Zuurendonk P, Westerterp-Plantenga M. Shortterm effects of a novel fat emulsion on appetite and food intake. Physiol Behav 2008,95:114–117. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397–415. Lawton CL, Burley VJ, Wales JK, Blundell JE. Dietary fat and appetite control in obese subjects: weak effects on satiation and satiety. Int J Obes Relat Metab Disord 1993;17:409–416. Logan CM, McCaffrey TA, Wallace JM, Robson PJ, Welch RW, Dunne A, Livingstone MB. Investigation of the medium-term effects of Olibratrade mark fat emulsion on food intake in non-obese subjects. Eur J Clin Nutr 2006;60:1081–1091. Maljaars J, Peters HP, Masclee AM. Review article: the gastrointestinal tract: neuroendocrine regulation of satiety and food intake. Aliment Pharmacol Ther 2007;26(Suppl 2):241–250. Seidell JC. Dietary fat and obesity: an epidemiologic perspective. Am J Clin Nutr 1998;67:546S–550S. Shahar DR, Yerushalmi N, Lubin F, Froom P, Shahar A, Kristal-Boneh E. Seasonal variations in dietary intake affect the consistency of dietary assessment. Eur J Epidemiol 2001;17:129–133. Stroebele N, De Castro JM. Effect of ambience on food intake and food choice. Nutrition 2004;20:821–838. Stunkard AJ. Current views on obesity. Am J Med 1996;100:230–236. Welch I, Saunders K, Read NW. Effect of ileal and intravenous infusions of fat emulsions on feeding and satiety in human volunteers. Gastroenterology 1985;89:1293–1297. Welch IM, Sepple CP, Read NW. Comparisons of the effects on satiety and eating behaviour of infusion of lipid into the different regions of the small intestine. Gut 1988;29:306–311.


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PART II

Protein based ingredients

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CHAPTER 5

The Role of Dairy Products and Dietary Calcium in Weight Management Lisa A. Spence, PhD, RD, and Raj G. Narasimmon, PhD

Abstract Overweight and obesity are global public health concerns. Excess body fat increases the risk of premature death, coronary heart disease, type 2 diabetes, hypertension, stroke, some types of cancer, and other debilitating conditions. The cause of overweight and obesity is multifactorial and successful prevention or treatment depends on multiple actions. Although attention has focused primarily on reducing energy (calorie) intake and/or increasing energy expenditure (physical activity), a promising beneficial role for dietary calcium and dairy products in weight management has emerged. Overall, the body of scientific evidence including human, clinical, observational, animal, and cellular studies supports a relationship between the consumption of dairy foods and weight management. While consumption of dairy foods has been shown to exert a greater impact than calcium alone, studies continue to examine the mechanism to explain this phenomenon, which appears to be multifactorial and may involve bioactive components found in dairy foods. While there is more to learn about dairy food consumption’s impact on weight management, the Dietary Guidelines recommend 3 servings of low-fat and fat-free milk or equivalent milk products (e.g., cheese, yogurt) daily as part of a healthy diet and stresses the importance of balancing calories consumed from foods and beverages with calories expended to achieve and maintain a healthy body weight.

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Introduction Overweight and obesity are global public health concerns (Wang and Lobstein, 2006; WHO, 2000). In the United States, statistics indicate that more than 66% of adults are overweight or obese and 17% of children aged 2–19 years are overweight (Ogden et al., 2006). If current trends continue, nearly half of the children in North and South America will be overweight by 2010 (Wang and Lobstein, 2006). Excess body fat increases the risk of premature death, coronary heart disease, type 2 diabetes, hypertension, stroke, some types of cancer, and other debilitating conditions. Because of these health outcomes, as well as the adverse economic consequences of overweight and obesity, numerous government programs are focused on obesity prevention. The cause of overweight and obesity is multifactorial and successful prevention or treatment depends on multiple actions. Although attention has focused primarily on reducing energy (calorie) intake and/or increasing energy expenditure (physical activity), a promising beneficial role for dietary calcium and dairy products in weight management has emerged. Several review articles have been published summarizing the observational and clinical data published to date and elucidating the mechanism of action (Barr, 2003; Heaney, 2003; Heaney et al., 2002; Major et al., 2008; Parikh and Yanovski, 2003; Schrager, 2005; St-Onge, 2005; Teegarden, 2003, 2005; Trowman et al., 2006; Zemel, 2001, 2002, 2003a, 2003b, 2005). One such review indicated that each 300 mg increase in calcium intake was associated with about 1 kg less body fat in children and as much as 3 kg lower weight in adults. These researchers also reported that increasing calcium intake by 2 servings of dairy products (600 mg calcium) per day could reduce the risk of being overweight by as much as 70% (Heaney, 2003). A recent review by Major et al. (2008) presented information by experts in the field of calcium/dairy and weight loss during a 2007 symposium. The review integrates current developments in calcium-related obesity research focusing on the effects of calcium and dairy consumption on (1) body weight, (2) adiposity, (3) weightloss intervention outcome, (4) lipid–lipoprotein profile, and (5) the risk of developing metabolic syndrome. Moreover, the review discusses the potential molecular mechanisms that explain the effects of dairy and calcium, such as increased adipocyte calcium concentrations and changes in lipolysis, lipogenesis, calcium intake and fat cell apoptosis, calcium intake and UCP2 expression, calcium intake on satiety, and calcium intake and fecal fat excretion.


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This chapter reviews the current scientific evidence, including human clinical interventions, observational studies, and animal research that has explored the relationship between the consumption of dairy foods and weight management as well as plausible mechanisms by which dairy products may favorably affect body weight, body fat, and lean mass. The chapter also addresses food application and patent activities.

Scientific Evidence on Efficacy and Mechanism of Action Randomized Clinical Trials Controlled feeding studies in humans are considered the “gold standard” for interventions and have provided the strongest evidence for a beneficial role of dairy foods and calcium on body weight and body fat. Since 1998, there have been several published reports (Bowen et al., 2005; Eagan et al., 2006; Gunther et al., 2005a; Harvey-Berino et al., 2005; Major et al., 2007; Summerbell et al., 1998; Thompson et al., 2005; Wagner et al., 2007; Zemel et al., 2004, 2005a, 2005b, 2009) of randomized trials designed to evaluate the effects of calcium and/or dairy product consumption on body weight and fat loss under caloric restriction in obese and overweight adults or changes in body composition under caloric maintenance in obese and normal-weight adults as the primary outcome. Some human studies (Boon et al., 2005a; Cummings et al., 2006; Gunther et al., 2005b; Jacobsen et al., 2005; Lorenzen et al., 2007; Melanson et al., 2005) have been conducted to compare the effect of increased calcium or dairy product consumption on energy expenditure, substrate oxidation, thermic effect of food, and/or fecal fat excretion to understand the mechanism by which calcium or dairy products may impact body weight and composition. In many of these studies, overweight or obese adults (males, females, Caucasians, African Americans) who followed moderately reducedcalorie diets for 12 or 24 weeks, and increased consumption of dairy foods from 1 serving or less per day (inadequate calcium) to ≥3 servings per day (adequate calcium), experienced enhanced body weight and/or body fat loss, reduced abdominal (trunk) obesity, and minimal loss of lean body mass compared to those consuming little or no dairy foods. Moreover, the intake of dairy foods had a substantially greater effect on both weight and fat loss compared to an equivalent amount of calcium alone.


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Importantly, three physiological and dietary conditions were common in those studies showing favorable weight-loss effects of dairy/calcium. First, all study subjects were obese or overweight. Second, the subjects’ habitual calcium intakes were inadequate ( 0.01, at month 4: group (low caffeine intake group receiving green tea vs. all other groups) × time (four-factor repeated measures ANOVA). (After Westerterp-Plantenga et al., 2005.)

group (Diepvens et al., 2005). Moderate use of caffeine is likely to make the green tea supplement ineffective (Westerterp-Plantenga et al., 2005). In a recent long-term weight-loss study from Thailand, obese people that consumed the green tea intervention (100 mg EGCG and 87 mg caffeine/day) lost significantly more weight within 12 weeks compared to the placebo group (2.7 vs. 2.0 kg) that ate the similar standardized meals during the entire study. REE was significantly increased after 12 weeks of green tea supplementation, which led to the body weight reduction (Auvichayapat et al., 2008). Caffeine Although caffeine seems to increase thermogenesis in the short term, greater weight loss was not achieved when consuming caffeine in comparison to a placebo in obese subjects in the long term (Pasman et al., 1997; Tremblay et al., 1988). The observation that a habitually high (>300 mg/day) caffeine intake group receiving a green tea–caffeine combination did not show greater body weight maintenance after body weight loss than


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a habitually high-caffeine group receiving placebo leads to the suggestion that sensitivity to caffeine may be lost over time (Westerterp-Plantenga et al., 2005). Increased SNS activity has been shown to lead to a decrease in energy intake (Bray, 1993). In men (but not in women), caffeine consumption (300 mg) appeared to reduce energy intake (by 22%) (Tremblay et al., 1988). Moreover, a positive relationship between satiety and daily caffeine intake, in men and women, was shown (Westerterp-Plantenga et al., 2005). Lopez-Garcia et al. studied the effect of caffeine on longterm weight change in a prospective study. In their cohort, they found that people who increased the caffeine consumption over 12 years gained less weight than those who decreased the caffeine consumption (Lopez-Garcia et al., 2006). Thus, caffeine may influence both EE and energy intake.

Mechanisms of Action Catechins in green tea inhibit the enzyme catechol-O-methyltransferase (COMT) that is present in almost every tissue and degrades catecholic compounds such as norepinephrine (NE) (Dulloo et al., 1999; WesterterpPlantenga et al., 2005). COMT decreases the hydrophilicity by methylation, followed by sulfation and glucuronidation to make the excretion in urine and bile possible (Shixian et al., 2006). NE cannot be degraded through the inhibition of COMT and consequently the sympathetic nerve system (SNS) will be stimulated continuously due to the presence of NE, which attaches to β-adrenoceptors and causes an increase in EE and fat oxidation (Diepvens et al., 2007; Westerterp-Plantenga et al., 2006). The SNS plays an important role in the regulation of energy homeostasis but the above-described phenomenon does not always appear equally clear in all ethnic groups. For instance, studies with Asian subjects seem to report more positive results than studies with Caucasian subjects. This may be caused by differences in relevant enzyme activity, causing differences in sensitivity for these ingredients. In that respect, Hodgson et al. (2006) stated that there is a wide variability in flavonoid O-methylation, a major pathway of flavonoid metabolism, by the enzyme COMT. The interindividual variability of the activity of COMT could vary as much as threefold (Hodgson et al., 2006). Moreover, there is evidence that there is a difference in COMT enzyme activity between ethnic groups (Palmatier et al., 1999). Asian populations have a higher frequency of the thermostable, high-activity enzyme, COMTH allele (Val/Val polymorphism) than the Caucasian populations. The Caucasian populations have a higher frequency of the thermolabile, low-activity enzyme, COMTL allele


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(Met/Met/Val polymorphism) (Palmatier et al., 1999). Fifty percent of Caucasians are homozygous for the COMTL allele (25%) and COMTH allele (25%). The other 50% is heterozygous (Met/Met polymorphism) (Palmatier et al., 1999). This may explain the difference in sensitivity to interventions with green tea–caffeine mixtures, and why, in some studies with Caucasian subjects, no effect was seen after ingestion of green tea. As caffeine is also present in green tea, its effect will also take place after green tea consumption. Caffeine affects the thermogenesis by inhibiting the enzyme phosphodiesterase. This enzyme degrades intracellular cyclic amino mono phosphate (cAMP) (Diepvens et al., 2007; Westerterp-Plantenga et al., 2006). Phosphodiesterase usually hydrolyses cAMP to AMP, but after consumption of caffeine, cAMP concentration rises and SNS activity will be increased and inactive hormone-sensitive lipase (HSL) will be activated, which promotes lipolysis (Acheson et al., 2004). The SNS activity and lipoysis are dependent on cAMP, because cAMP activates the protein kinase A (Belza et al., 2007). Besides the inhibition of phosphodiesterase, caffeine also affects the thermogenesis through the stimulation of substrate cycles such as the Cori cycle and the FFA-triglycreride cycle (Diepvens et al., 2007; Westerterp-Plantenga et al., 2006). Caffeine is a methylxanthine, which has a thermogenic impact. In the Cori cycle, lactate moves from the muscles to the liver where it will be converted into pyruvate. The pyruvate will be converted to glucose by the enzyme lactate dehydrogenase and circulate back to the muscles via the blood (Diepvens et al., 2007; Westerterp-Plantenga et al., 2006). Acheson et al. showed that FFA turnover and lipid oxidation are increased after the consumption of caffeine but that it requires a large increase in FFA turnover to have a small increase in lipid oxidation. Nonoxidative lipid turnover, the hydrolysis and reesterification of triacylglycerol, is greater than the increase in oxidative lipid disposal (Acheson et al., 2004). They also found that caffeine antagonizes the inhibitory effects of adenosine on lipolysis via adenylyl cyclase. Nonadrenergic thermogenic mechanisms can also be involved, as caffeine antagonizes the ryanodine receptor, the calcium ion release channel of sarcoplasmatic reticulum in skeletal muscle that for instance increases glycolysis and ATP turnover after stimulation (Acheson et al., 2004). Catechins and caffeine inhibit two enzymes, which interrupt the pathway of NE-activated thermogenesis (Kao et al., 2000b). As SNS activity is determined by the concentration of NE, more NE means a higher activity and increased EE. SNS activity regulates the resting metabolic rate, which is the largest component of the daily EE. NE makes it possible to increase the usage of ATP through ion pumping and substrate cycling


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(Diepvens et al., 2007). The rate of mitochondrial oxidation is also involved in the increased thermogenesis due to the poor coupling of ATP synthesis, which leads to heat production. Catechins also have a direct effect on the gene expression of different uncoupling proteins (UCPs) that influence the thermogenesis with the production of heat (Klaus et al., 2005). Gene expression of the UCPs also increases when cAMP activates the protein kinase A, after the inhibition of phophodiesterase by caffeine (Lowell and Spiegelman, 2000). The protein kinase A stimulates HSL, which increases the concentration of free fatty acids by the conversion of triglycerides. UCP activity will be enhanced through this (Lowell and Spiegelman, 2000). The increase in EE is accompanied by a change in substrate oxidation as Dulloo et al. showed an increase in fat oxidation after the supplementation of green tea (Dulloo et al., 1999). Another mechanism is triggered by the tea catechins that block the nuclear factor-κ B (NFκB) activation by inhibiting the phosphorylation of IκB (Yang et al., 2001). NFκB is an oxidative stress sensitive transcription factor that regulates the expression of several genes, which are important in cellular responses such as inflammation and growth (Yang et al., 2001). NFκB is no longer able to inhibit the peroxisome proliferator activated receptors (PPARs) that are important transcription factors for lipid metabolism (Murase et al., 2002). The mRNA expression of lipid-metabolizing enzymes such as acyl-CoA oxidase (ACO) and medium-chain acyl-CoA dehydrogenase (MCAD) is upregulated. ACO is a peroxisomal β-oxidation enzyme and MCAD is a mitochondrial β-oxidation enzyme in the liver (Murase et al., 2002). The upregulation of these lipid-metabolizing enzymes makes it clear that β-oxidation activation after the supplementation of tea catechins is enhanced followed by an increase in fat oxidation.

Safety of Caffeine and Green Tea Administration Caffeine appears to be a safe thermogenic agent for weight control. In adults, the short-term lethal dose for caffeine is estimated at 5–10 g/day (either intravenously or orally), which is equivalent to 75 cups of coffee, 125 cups of tea, or 200 cola beverages (Curatolo and Robertson, 1983). Long-term ingestion of caffeine has been suggested to have some minor adverse effects on human health. Astrup et al. (1990) observed only small and insignificant changes in blood pressure and pulse rate after 100 and


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200 mg caffeine. In contrast, 400 mg caffeine significantly increased systolic and diastolic blood pressure by an average value of 6.3 mm Hg. Furthermore, after 400 mg caffeine, significantly more subjects reported side effects such as palpitation, anxiety, headache, restlessness, and dizziness compared with placebo (Astrup et al., 1990). Robertson et al. (1978) administrated 250 mg oral caffeine to nine subjects who were not used to coffee. Systolic blood pressure increased 10 mm Hg 1 hour after caffeine consumption. Heart rate showed a decrease after the first hour followed by an increase above baseline after 2 hours (Robertson et al., 1978). However, in a subsequent study that examined the chronic effects of caffeine ingestion (150 mg/day for 7 days), tolerance to these effects was developed after 1–4 days (Robertson et al., 1981). Thus, no long-term effects of caffeine on blood pressure, heart rate, or plasma rennin activity were demonstrated. Furthermore, in the short term, Bracco et al. (1995) did not find a significantly altered heart rate during the day after 4 mg caffeine per kg body weight was consumed five times daily. Accordingly, the use of caffeine is relatively safe, as it is quite certain that, although acute caffeine consumption may alter some cardiovascular variables, chronic ingestion of caffeine has little or no health consequences. Green tea has been widely consumed in China and Japan for many centuries and is regarded as safe. A possible side effect of green tea consumption is a minor increase in blood pressure as seen by BerubeParent et al. (2005). They observed a nonsignificant increase (7 mm Hg) in 24-hour systolic blood pressure accompanied by a significant increase (5 mm Hg) in 24-hour diastolic blood pressure. No increase in heart rate was seen (Berube-Parent et al., 2005). This small short-term increase in blood pressure induced by green tea might be neglected since systolic blood pressure, diastolic blood pressure, and heart rate were not affected by green tea in other short-term (Dulloo et al., 1999) or long-term research (Chantre and Lairon, 2002; Diepvens et al., 2005).

Food/Supplement Applications Caffeine and green tea are known to enhance fat oxidation and EE, which makes them excellent (slimming) ingredients for people who want to lose weight or maintain their weight. These ingredients are also known to have a positive effect on one’s health as the antioxidants protect against different types of cancer, cardiovascular diseases, and neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s. They are also


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offered as capsules and powders and for instance used by athletes to enhance their performances, as they can give them an energy boost.

Patent Activities 1. Document ID: WO2003090673A2 Title: COMPOSITIONS AND METHODS FOR PROMOTING WEIGHT LOSS, THERMOGENESIS, APPETITE SUPPRESSION, LEAN MUSCLE MASS, INCREASING METABOLISM AND BOOSTING ENERGY LEVELS, AND USE AS A DIETARY SUPPLEMENT IN MAMMALS Assignee: RTC RES & DEV LLC 2. Document ID: WO2007056133A2 Title: HERBAL COMPOSITION FOR WEIGHT MANAGEMENT Assignee: INDFRAG LTD 3. Document ID: WO2007101349A1 Title: COMPOSITIONS AND METHODS FOR INCREASING ADIPOSE METABOLISM, LIPOLYSIS OR LIPOLYTIC METABOLISM VIA THERMOGENESIS Assignee: HHC FORMULATIONS LTD 4. Document ID: WO2008006082A2 Title: ENERGY ENHANCING FORMULATION Assignee: BARRON JON 5. Document ID: WO2008028268A1 Title: DIET SUPPLEMENT FOR CAUSING WEIGHT LOSS COMPRISING CISSUS QUANDRANGULANS, GREEN TEA AND CAFFEINE Assignee: MULTI FORMULATIONS LTD 6. Document ID: US20020192308A1 Title: Method and composition for controlling weight

Information on Global Suppliers Green tea and caffeine (coffee, soft drinks, energy drinks) are available in every supermarket worldwide. Capsules and powders are also available in commercial stores and on the internet. One of the world’s leading companies in green tea is the Japanese Kao Corporation. Nestlé is a big company that deals with caffeine as it exploits the world’s largest coffee brand.


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CHAPTER 11

Mechanisms of (−)Epigallocatechin-3-Gallate for Antiobesity Hyun-Seuk Moon, PhD, Mohammed Akbar, PhD, Cheol-Heui Yun, PhD, and Chong-Su Cho, PhD

Abstract It has long been recognized that obesity is major risk factor for numbers of disorders including diabetes, hypertension, and heart diseases. For these, adipocytes play a central role in maintaining lipid homeostasis and energy balance in vertebrates by storing triacylglycerols (TGs) and releasing free fatty acids (FFAs) in response to changes in energy demands. Last few years, numerous studies regarding green tea catechins (GTCs) are reported to exhibit a variety of biological activities including cancer prevention and cardiovascular health. Furthermore, the obesity-preventive effects of green tea and its main constituent especially (−)-epigallocatechin-3-gallate (EGCG) are widely supported by results from epidemiological, cell culture, animal, and clinical studies. In this review, the biological activities and multiple mechanisms of EGCG in vitro and in vivo studies including animal models and clinical observations are explained.

Introduction Adipocytes and Obesity It is well known that adipocytes play a critical role in maintaining lipid homeostasis and energy balance by either storing triacylglycerols (TGs) or 177


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releasing free fatty acids (FFAs) dependent on changes of energy demands (Fruhbeck et al., 2001). In the industrialized countries, obesity becomes a major risk factor for numbers of disorders such as diabetes, hypertension, and heart disease (Farmer and Auwerx, 2004; Kelly and Goodpaster, 2001; Lee et al., 2005; Lewis et al., 2002). Also, several lines of evidence have suggested that TG accumulation in skeletal muscles and pancreatic islets is causally related to the insulin resistance together with pancreatic β-cell dysfunction in obese patients (Kelly and Goodpaster, 2001; Lewis et al., 2002). The development of obesity can be characterized by an increased number of fat cells and the contents of lipids due to the processes so called mitogenesis and differentiation, which are regulated by genetic, endocrine, metabolic, neurological, pharmacological, environmental, and nutritional factors (Farmer and Auwerx, 2004; Lewis et al., 2002; Unger and Zhou, 2001). Accordingly, an understanding of the mechanism by which particular nutrients affect the mitogenesis of preadipocytes and their differentiation to adipocytes would help to understand, and therefore prevent the initiation and progression of obesity and its associated diseases (Unger and Zhou, 2001).

Green Tea After water tea is the second most widely consumed beverages in the world, and its origins date back thousands of years (Rusznyak and SzentGyorgyi, 1936). Green tea, prepared by drying fresh tea leaves, contains a number of bioactive components, including polyphenols, caffeine, amino acids, and other trace compounds such as lipids and vitamins (Safe, 2001). It has been suggested that the health-promoting effects of green tea are mainly attributed to its polyphenol content (Roberts, 1953; Rusznyak and Szent-Gyorgyi, 1936; Safe, 2001). In fact, green tea is a rich source of polyphenols, especially flavanols and flavonols, which represent approximately 30% of dry weight of its fresh leaf (Ahmad and Mukhtar, 1999; Lin et al., 1999; Roberts, 1953; Safe, 2001). Catechins are the predominant form of the flavanols and mainly comprised epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC) (Ahmad and Mukhtar, 1999; Roberts, 1953). Not only they have unique chemical structures (Fig.11.1) and are major ingredients of unfermented tea (Hung et al., 2005) but they have been also found to possess widespread biological functions and health benefits (Chung et al., 2003; Kong et al., 2000; Lambert and Yang, 2003; Mukhtar and Ahmad, 2000; Riemersma et al., 2001). Recently, it is becoming clear that


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Mechanisms of (−)-Epigallocatechin-3-Gallate

179

OH 4´

OH

5´

R1

B HO

O

7

2

A 5

3

OR2

G=galloyl:

OH

OH C

C

OH

O OH

(−)Epicatechin (EC) (−)Epigallocatechin (EGC) (−)Epicatechin-3-gallate (ECG) (−)Epigallocatechin-3-gallate (EGCG)

R1

R2

g/mol

H OH H OH

H H G G

290 306 442 458

Figure 11.1. Structures of four major green tea catechins. Differences among these catechins occur in the number of hydroxyl groups, the presence of a galloyl group, and the molecular weight (Hung et al., 2005; reprinted with permission).

many of the aforementioned beneficial effects of green tea were attributed to its most abundant catechin, EGCG (Ahmad and Mukhtar, 1999; Lin et al., 1999; Roberts, 1953). Indeed, it has been shown that EGCG lowers the incidence of various cancers (Ahmad and Mukhtar, 1999; Lin et al., 1999; Mitscher et al., 1997; Roberts, 1953), collagen-induced arthritis (Yang and Wang, 1993), oxidative stress-induced neurodegenerative disease (Haqqi et al., 1999), and streptozotocin-induced diabetes (Mendel and Youdim, 2004). Also, it has been clearly demonstrated that EGCG or EGCG-containing green tea extract reduces food uptake, lipid absorption, and blood TGs, cholesterol, and leptin levels, as well as stimulating energy expenditure, fat oxidation, high-density lipoprotein (HDL) levels, and fecal lipid excretion (Safe, 2001; Song et al., 2003).

The Aim of This Review During the last decades, the obesity-preventive effects of green tea and its main compound EGCG are widely supported by results from epidemiological, preclinical, and clinical studies. This review focuses on in vitro


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and in vivo studies investigating the antiobesity effects of green tea or isolated green tea components and attempts to explore the underlying mechanisms. The possible relevance of each of the proposed mechanism on human obesity prevention is also discussed. The mechanisms for antiobesity discussed in this review may possibly be utilized in the further research and therapeutic treatment of patients with obesity and its related disease.

Antiobesity Mechanisms of EGCG Antiadipogenic Effect of EGCG via Extracellular Signal-Regulated Kinase (ERK)-Dependent Signaling Pathway Mitogen-activated protein kinases (MAPKs) are serine/threoninespecific protein kinases composed of extracellular signal-related kinases (ERK) and c-Jun-N-terminal kinases (JNK) and p38 that respond to extracellular stimuli (e.g., mitogens) and regulate various cellular activities, such as gene expression, mitosis, differentiation, and cell survival/apoptosis. The activation of MAPK results in regulation of gene expression by phosphorylation of a variety of transcription factors and modification of their transcriptional efficiencies in a variety of cell types (Pearson et al., 2001). Importantly, in adipocytes, both ERK and JNK can phosphorylate peroxisome proliferator-activated receptor γ (PPARγ), which results in repression of its transcriptional activation potential and adipogenesis (Ahmad and Mukhtar, 1999). In relation to this action, EGCG has been proposed to serve as signal elements in several types of cells where EGCG may regulate cell growth (Ahmad and Mukhtar, 1999; Yang and Wang, 1993) and may modulate the mitogenic and adipogenic signalings of IGF-I in 3T3-L1 preadipocytes (Levites et al., 2002). In addition, the antiadipogenic effect of EGCG appears to be important not only in reducing adipocyte differentiation (hypertrophy) but also in inhibiting adipocyte proliferation (hyperplasia), suggesting that ERK1/2, enzymes that involved in the control of cell cycle, is required for these inhibitory effects (Hung et al., 2005). Supporting this hypothesis, Hung et al. (2005) reported that EGCG induced a decrease in phosphorylated ERK1/2 in 3T3-L1 preadipocytes but did not alter the total levels of MEK1, ERK1/2, p38, phospho-p38, JNK, or phospho-JNK (Fig.11.2), suggesting that EGCG acts specifically on a phosphorylation of the ERK1/2. This contention is also partially supported


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Figure 11.2. Effects of EGCG on ERK1/2, phospho-ERK1/2 and MEK1 in 3T3-L1 preadipocytes (day 3). (a) Time-dependent effect of EGCG at 50 µM was observed. (b) Dose-dependent effect of EGCG was observed after 4 hours of treatment. (c) EGCG at 50 µM altered MEK1 activity as indicated by decreased phospho-ERK1/2, which was dependent on the growth phases of cells after 4 hours of treatment. Day 1, the day when cells were plated; latent, day 3; log-phase, day 5 (confluent). The kinases were measured by Western blot analysis and then expressed after normalization to β-actin. Data are expressed as mean ± SE from triplicate determinations. In some data, SE bars are too small to be seen. * indicates p < 0.05 when compared to the control (Hung et al., 2005; reprinted with permission).


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by the fact that exposure (24 or 48 hours) to EGCG induced a decrease in the phosphorylated ERK1/2 of preadipocytes without altering total levels of MEK1 or ERK1/2 proteins (Levites et al., 2002).

Antiadipogenic Effect of EGCG via Resistin (RSTN)-Modulated Adipogenesis Adipokines, mainly produced by adipocytes, are active participants in the regulation of inflammation (Arner, 2005). Among them, resistin (RSTN), known as an adipocyte-specific secretory factor (ADSF), is implicated to modulate insulin resistance in rodents (Adeghate, 2004). Interestingly, RSTN is expressed in white adipose tissue in mouse, but mainly in leukocytes in human. Steppan et al. reported that RSTN has an inhibitory effect on insulin-stimulated glucose uptake in differentiated 3T3-L1 adipocytes (Steppan et al., 2001). Recent study suggested that intracellular RSTN protein significantly decreased in the presence of 100 µM EGCG 3 hours after treatment, whereas the release of the RSTN protein has no significant change (Liu et al., 2006), suggesting that EGCG may modulate the distribution of RSTN protein.

Antiadipogenic Effect of EGCG via Cyclin-Dependent Kinase 2 (CDK 2)-Dependent Signaling Pathway It has been shown that EGCG downregulated adipocyte differentiation through the CDK2 signaling pathway (Hung et al., 2005). These results suggested that the antimitogenic effect of EGCG on 3T3-L1 preadipocytes is dependent on the ERK MAPK and cyclin-dependent kinase 2 (CDK2) pathways and is likely mediated through decreases in their activities. Also, Wu et al. reported that the apoptotic effect of EGCG on 3T3-L1 preadipocytes is dependent on the Cdk2 and caspase-3 pathways and is likely mediated through alterations in their activities (Wu et al., 2005), suggesting that decreases in Cdk2 activity by EGCG may be due to its effect on this particular member of the CKI family. However, there are very limited studies between EGCG and CDK. In vivo study suggested that CDK2 activity can be regulated by the association of stimulatory proteins such as cyclin E (Morgan, 1995). Hence, more investigations are needed to clarify whether the production of cyclin E protein and its association


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with CDK2 can be altered by EGCG and thereafter resulting decreases in CDK2 activity.

Antiadipogenic Effect of EGCG via Activation of AMP-Activated Protein Kinase (AMPK) AMPK is known to play an important role in energy homeostasis by coordinating number of effectors responses in ATP-depleting metabolic states such as ischemia/reperfusion, hypoxia, heat shock, oxidative stress, and exercise (Kemp et al., 2003; Morgan, 1995). Moreover, AMPK promotes oxidation of fatty acid and inhibits lipid synthesis in cells through phosphorylation and inhibition of acetyl-CoA carboxylase (ACC) activity (Jaleel et al., 2006; Shaw et al., 2004; Xie et al., 2006). The persistent activation of AMPK has been shown to be linked to p53-dependent cellular senescence, suggesting its role as an intrinsic regulator of the cell cycle (Jones et al., 2005). Moreover, AMPK cascades have emerged as novel targets for the treatment of obesity and type II diabetes (Luo et al., 2005; Meisse et al., 2002; Song et al., 2002). Hwang et al. (2005) suggested that several naturally occurring compounds including EGCG or capsaicin have potential antiobesity effects by activation of AMPK and inhibition of adipocyte differentiation in 3T3-L1 cells. This result indicated that AMPK activation is necessary for the inhibition of adipocyte differentiation by EGCG and capsaicin. Furthermore, Collins et al. reported that EGCG suppresses hepatic gluconeogenesis through ROS, CaMKK, and AMPK (Collins et al., 2007). Hence, the mechanism that affects AMPK regulation after EGCG treatment could be a promising target for the development of strategies to treat obesity.

Antiadipogenic Effect of EGCG via Regulation of Reactive Oxygen Species (ROS) Generally, ROS has been suggested as upstream molecules of AMPKactivated signals (Collins et al., 2007; Giakoustidis et al., 2008; Kemp et al., 2003; Meng et al., 2008; Qanungo et al., 2005; Yao et al., 2008). In fact, Hwang et al. reported that genistein inhibits adipocyte differentiation and the induction of adipocyte apoptosis through the activation of AMPK paralleled with the generation of ROS, and this effect was similar to that of EGCG treatment (Hwang et al., 2005). Therefore, one of the AMPK activation mechanisms was suspected to be ROS, which was supported by


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reports that various therapeutic effects in naturally occurring compounds were mediated by the release of ROS (Qanungo et al., 2005). Hwang et al. have shown that genistein induced ROS generation significantly, which led to AMPK activation, and these effects were abolished by its inhibitor, NAC (5 mM) treatment (Hwang et al., 2005). These results indicate that ROS is necessary for AMPK activation in the inhibitory process of adipocyte differentiation by phytochemicals in 3T3-L1 cells. Recent study also showed that EGCG at relatively low and nontoxic concentration (equal or less than 1 µM) inhibited glucose production by hepatic gluconeogenesis mediated by AMPK activation through Ca2+ /calmodulin-dependent protein kinase kinase (CaMKK) and ROS (Giakoustidis et al., 2008). Meng et al. investigated EGCG for its antiaging effect on human diploid fibroblasts (HDF). In this study, HDF treated with EGCG at 25 and 50 µM for 24 hours dramatically increased catalase, superoxide dismutase (SOD)1, SOD2, and glutathione peroxidase gene expressions and their enzyme activities. Furthermore, these activities appeared to be necessary to protect HDF against hydrogen peroxide (H2 O2 )-induced oxidative damage, accompanied with decreased accumulation of intracellular ROS and well-maintained mitochondrial integrity (Meng et al., 2008).

Antiadipogenic Effect of Green Tea via Inhibition of Lipogenic Enzymes GTCs are known to possess antilipogenic activity (Kao et al., 2006). They can inhibit the activity and/or expression of lipogenic enzymes, such as ACC, fatty acid synthase (FAS), malic enzyme (ME), glucose-6phosphate dehydrogenase (G6PDH), glyceol-3-phosphate dehydrogenase (G3PDH), and stearoyl-CoA desaturase-1 (SCD-1) (Table 11.1) (Ahmad and Mukhtar, 1999; Crespy and Williamson, 2004; Kao et al., 2006; Lin et al., 1999). ACC involves the rate-limiting step in fatty acid synthesis for catalyzing the conversion of acetyl-CoA to malonyl-CoA (Kimura et al., 1983). When ECG or EGCG from green tea was incubated with rat liver ACC, they (with Ki of 310 µM) inhibited the activity of ACC (Kimura et al., 1983). However, such activity was not observed when (+)-catechin, EC or EGC, was used. A recent report also showed that EGCG supplementation downregulates ACC mRNA expression in obese mice (Ahmad and Mukhtar, 1999). It has also been reported that when EGCG was incubated with chicken FAS, the second enzyme to catalyze the conversion of malonyl-CoA to fatty acyl-CoA, it inhibited FAS activity with an IC50 of 52 µM (Wang


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Table 11.1. EGCG inhibition of lipid-related enzymes in cell-free systemsa Enzymes Lipogenic enzymes ACC Aromatase FAS Lanosterol 14α-demethylase Oxidosqualene: lanosterol cyclase Squalene epoxidase Lipolytic enzymes GLb PL Oxidoreductase Glycyrhizin-binding lipoxygenase Lipoxygenase Type 1 5α-reductase Type 2 5α-reductase Others COMT

IC50 (µM) 310 60 52 >100 >100 0.7 10 0.34–11 10 10 15 74 0.2

Sources: Kao et al., 2006; reprinted with permission. a Activity and expression of some enzymes that have been found to be affected by tea catechins in cell or animal systems include ACC, FAS, ME, G6PDH, G3PDH, SCD1, acyl-CoA oxidase, medium-chain acyl CoA dehydrogenase, UCP2, UCP3, fatty acid translocase, carnitine palmitoyltransferase, and HSL. b The unit is expressed as milligrams of green tea extract per gram of tributyrin substrate.

and Tian, 2001). Generally, inhibitory activity of FAS by EGCG depends on reversible fast-binding inhibition and irreversible slow-binding inactivation (Wang and Tian, 2001). Because FAS shows high levels of activity in LNCaP human prostate cancer cells, EGCG treatment at 100 µM for 24 hours inhibited 52% FAS activity (Brusselmans et al., 2003). In addition, EGCG is reported to suppress FAS mRNA and protein levels in MCF-7 breast cancer cells suggested that EGCG signaling may be involved in the downregulation of the EGF receptor and its downstream Akt and Sp-1 proteins (Yeh et al., 2003). Moreover, a decrease in the expression of hepatic ME and G6PDH, which generate NADPH for fatty acid biogenesis, has also been observed in obese mice when treated with EGCG (Ahmad and Mukhtar, 1999). Furthermore, the activity and expression of G3PDH involving a step in TG biosynthesis are decreased by EGCG treatment (Mochizuki and Hasegawa, 2004). Also, it was found that gene expression of SCD1, utilized for the synthesis of monounsaturated fatty


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acids by liver and adipose tissue, was suppressed in EGCG-treated obese mice (Ahmad and Mukhtar, 1999). Overall, green tea, EGCG in particular, appears to reduce fatty acid and TG synthesis by inhibiting lipogenic enzymes, and this may explain its hypolipidic effects.

Antiadipogenic Effect of Green Tea via Downregulation of Adipocyte Marker Proteins and Its Target Genes Generally, the enforced expression of PPARγ and C/EBPα stimulates adipogenesis in NIH 3T3 fibroblasts, suggesting the essential role of these transcription factors in regulating adipogenesis (Chu et al., 1995; Dalei and Lazar, 1997). In fact, PPARγ2 and C/EBPα are found almost exclusively in the adipose tissue and have been linked to the adipocyte differentiation (Hwang et al., 1997), which could play a crucial role both in the induction of adipose-specific genes and in the manifestation of the mature adipose phenotype. Furthermore, the combined expression of PPARγ and C/EBPα has synergistic effects in promoting fat cell conversion in myoblasts (Brown et al., 2003; Moon et al., 2006), indicating that they are very important for fat accumulation. Also, these transcription factors coordinate the expression of genes involved in creating and maintaining the adipocyte phenotype, including aP2 (Chu et al., 1995). The aP2, a member of intracellular lipid binding protein family, is involved in the formation of atherosclerosis predominantly through the direct modification of cholesterol trafficking and inflammatory responses in the macrophages (Chu et al., 1995; Dalei and Lazar, 1997). By contrast, it was demonstrated that EGCG significantly downregulated the expression of adipocyte maker genes during adipocyte differentiation (Yang and Wang, 1993), indicating that the negative impact of EGCG on adipogenesis was accompanied by the reduction of PPARγ2 protein in 3T3-L1 cells coincide with the attenuation of C/EBPα expression. Because PPARγ is one of the key transcription factors in the induction of adipogenesis and lipid accumulation (Brown et al., 2003; Moon et al., 2006), EGCG-induced downregulation of PPARγ expression is likely to suppress the lipid accumulation and adipocyte differentiation (Haqqi et al., 1999; Kao et al., 2000; Mendel and Youdim, 2004; Song et al., 2003). On the other hand, TG hydrolysis proportionally released glycerol and FFA from adipocytes, and the glycerol release caused the lipolysis in the adipocytes (Moussalli et al., 1986). Certain natural compounds such as conjugated linoleic acid (CLA) and forskolin-induced lipolysis in adipocyte models (Wolfram et al., 2006b).


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In fact, we previously reported that CLA had an antiadipogenic effect and induced lipolysis in 3T3-L1 cells (Moon et al., 2006). It is to note from another study that GTCs strongly reduced adipocyte differentiation but did not induce lipolysis (Wolfram et al., 2006a), indicating that the antiadipogenic effects of EGCG have no direct relation with changes of lipolysis.

Insulin-Potentiating Activity by Green Tea In addition to the antiadipogenic effects of EGCG on adipocyte marker protein expression, Wu et al. reported that, after 12 weeks of green tea supplementation, the fasting plasma glucose and insulin levels in the green tea group were significantly lower than those in the control group (Wu et al., 2004). As shown in Fig. 11.3, during the 2 hours following glucose ingestion, no difference was seen in the plasma glucose levels between the two groups. However, the plasma insulin levels of the group fed with green tea at all time points were significantly (p < 0.05) lower than those in the control group. In fact, the AUCs for plasma glucose and insulin were 336

Control Green tea

(b) 50 Plasma insulin (µU/mL)

Plasma glucose (mg/dL)

(a) 250 200 150 100

* 50

40 30 20

*

*

10

* *

* 0

0 0

30

60

90 120 150

Time (min)

0

30

60

90 120 150

Time (min)

Figure 11.3. Changes in plasma levels of glucose (a) and insulin (b) in rats in response to an oral glucose tolerance test (2 g of glucose/kg of BW) performed after 12 weeks with or without green tea supplementation. Values are shown as the mean ± SD. * indicates p < 0.05 when compared to the control group (Wu et al., 2004; reprinted with permission).


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± 11 mg h/dL and 38 ± 10 µU h/mL, respectively, in the group fed with green tea, whereas 346 ± 13 mg h/dL and 60 ± 18 µU h/mL, respectively, in the control group. No significant difference was found between the two groups in the AUC for plasma glucose (p = 0.260); however, the AUC for insulin in the group fed with green tea was significantly lower (p = 0.004) than the control group, demonstrating that the green tea causes increase of insulin sensitivity. These results indicated that green tea supplementation in the form of regular tea infusion could increase insulin sensitivity by increasing the glucose uptake. It is believed that the beneficial effects of green tea are due to the polyphenols, the principal active ingredients. It provides the protection against oxidative damage and antibacterial, antiviral, anticarcinogenic, and antimutagenic activities; however, it may also increase insulin activity (Wu et al., 2004). Several compounds found in green tea were also shown to enhance insulin activity, for instance, EGCG as the greatest activity, followed by ECG, tannins, and theaflavins (Anderson and Polansky, 2002; Carobbio et al., 2004; Wu et al., 2004). Supporting these results, Anderson et al. reported that the insulinpotentiating activity in green and oolong tea was mainly due to EGCG (Table 11.2) (Anderson and Polansky, 2002). These data demonstrated that the increased insulin together with its activity of the tea leaves is predominantly due to the presence of the active ingredient EGCG. Insulin secretion by pancreatic β cells is stimulated by glucose, amino acids, and other metabolic fuels (Carobbio et al., 2004). Li et al. reported that EGCG does not affect glucose-stimulated insulin secretion under high-energy conditions when glutamate dehydrogenase (GDH) is fully inhibited. They also showed that EGCG acts in an allosteric manner independent of their antioxidant activity and that the β-cell

Table 11.2. Insulin activity ratios of fractions from Oolong teaa Fraction Time (minutes) 2.5–6 6–13 13–20 20–23 23–28

Insulin Activity Ratio

Fraction Time (minutes)

Insulin Activity Ratio

1.5 1.2 1.3 4.5 1.0

38–44 44–47 47–52 52–60 60–68

1.1 0.9 1.3 1.4 1.3

Sources: Anderson et al., 2002; reprinted with permission. a Fractions were collected as described for the chromatogram. Individual fractions were concentrated by rotoevaporation to 0.5 mL and diluted fivefold in water prior to assay.


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stimulatory effects are directly correlated with glutamine oxidation (Li et al., 2006).

Epidemiological Observation of Green Tea and Clinical Studies Although some epidemiological studies have failed to provide clearcut evidence for a link between tea consumption and body weight (Kono et al., 1996), several studies have shown that tea intake is associated with decreased serum concentrations of total cholesterol and lipoprotein. For example, Tokunaga et al. reported that green tea consumption was inversely associated with serum levels of total cholesterol and LDL, but not with body weight index, HDL, and TG (Tokunaga et al., 2002). In another study with men over 40 years of age, higher levels of green tea consumption were associated with a proportional increase of HDL coincide with a proportional decrease of LDL and serum concentrations of total cholesterol and TG, but not with the body weight index (Imai and Nakachi, 1995). In a recent clinical study, green tea extract containing 25% EGCG exerted reduction of body weight (4.6%) and waist circumference (4.5%) in moderately obese patients 3 months after treatment (Chantre and Lairon, 2002). Also, Nagao et al. (2005) reported that the subjects who ingested one bottle of oolong tea containing 690 mg GTCs/day for 12 weeks had a lower body weight, body weight index, waist circumference, body fat mass, and subcutaneous fat area than did the subjects who ingested one bottle of oolong tea containing 22 mg catechins/day (Table 11.3). These early studies indicated the beneficial effects of GTCs to reduce body weight. Also, Nakagawa et al. clearly demonstrated that when 18 healthy Japanese men were given a green tea extract containing 254 mg, their plasma level of EGCG reached 0.27 nM in 1 hour after administration, while plasma phospholipids, total cholesterol, and TG did not change. However, the plasma phatidycholine hydroperoxide level decreased from 74 pM in controls compared to 45 pM in EGCG-treated subjects, suggesting that tea catechins are as effective as antioxidants (Nakagawa et al., 1999). It is to note that there are controversial observations on the regulation of energy expenditure and fat oxidation by green tea in human. In fact, according to a respiratory chamber study, ten healthy men had a green tea extract that contains 50 mg caffeine and 90 mg EGCG at breakfast,

190

Weight (kg)b,c Control group GTE group BMI (kg/m2 )b,c Control group GTE group Waist (cm)b–d Control group GTE group Hip (cm)b Control group GTE group Body fat mass (kg)b,c Control group GTE group Lean body mass (kg)b Control group GTE group 72.9 ± 1.3 72.6 ± 1.7 24.7 ± 0.4 24.4 ± 0.4 86.7 ± 1.1 86.6 ± 1.4 95.9 ± 0.7 97.0 ± 0.9 18.8 ± 0.9 19.2 ± 0.9 54.1 ± 0.7 53.4 ± 1.0

25.0 ± 0.4 24.9 ± 0.4 87.8 ± 1.1 87.9 ± 1.4 97.0 ± 0.8 97.4 ± 0.9 19.5 ± 1.0 19.7 ± 0.8 54.3 ± 0.7 54.2 ± 1.1

Four Weeks

73.8 ± 1.3 73.9 ± 1.8

Initial

53.9 ± 0.7 54.1 ± 1.1

18.8 ± 1.0 18.0 ± 0.9

95.8 ± 0.8 96.0 ± 1.1

53.7 ± 0.7 53.2 ± 1.0

18.8 ± 1.1 18.3 ± 0.9

95.8 ± 0.8 96.1 ± 1.1

86.2 ± 1.2 84.5 ± 1.3

24.6 ± 0.4 24.1 ± 0.4

72.5 ± 1.4 71.5 ± 1.7

Twelve Weeks

−0.6 ± 0.3 −1.0 ± 0.4

−0.7 ± 0.3 −1.4 ± 0.3

−1.1 ± 0.3 −1.3 ± 0.3

−1.6 ± 0.4 −3.4 ± 0.5

−0.4 ± 0.1 −0.8 ± 0.2

−1.3 ± 0.3 −2.4 ± 0.5

Change at Twelve Weeks

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86.6 ± 1.1 85.5 ± 1.3

24.6 ± 0.4 24.3 ± 0.4

72.7 ± 1.4 72.2 ± 1.7

Eight Weeks

Table 11.3. Changes in anthropometric variables and body composition after consumption of either control or high-catechin beverages for 12 weeksa

P1: SFK/UKS P2: SFK c11 BLBS044-Cho October 15, 2009 Printer Name: Yet to Come

26.2 ± 1.5 25.9 ± 1.8 246.4 ± 12.7 232.1 ± 9.9 84.5 ± 5.0 73.2 ± 5.3 161.9 ± 11.0 158.8 ± 8.3

25.3 ± 1.3 26.3 ± 1.6 254.2 ± 13.1 246.3 ± 11.2 88.9 ± 6.5 79.2 ± 5.4 165.3 ± 10.7 167.1 ± 8.7

167.3 ± 11.0 158.7 ± 7.9

87.0 ± 5.2 73.0 ± 5.3

254.3 ± 13.6 231.7 ± 11.1

25.7 ± 1.4 24.6 ± 1.5

−4.1 ± 4.1 −16.7 ± 3.0

−2.4 ± 2.7 −10.1 ± 4.0

−6.7 ± 5.8 −26.7 ± 6.0

−1.3 ± 0.7 −3.3 ± 0.7

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Sources: Nagao et al., 2005; reprinted with permission. a All values are x ± SEM. GTE, green tea extract; TFA, total fat area; VFA, visceral fat area; SFA, subcutaneous fat area. Control group, n = 18; GTE group, n = 17. The initial values did not differ significantly between groups. Data from weeks 0, 4, 8, and 12 were compared by using two-factor repeated-measures ANOVA with time and group. b Significant effect of time from week 0 to week 12, p < 0.01. c Significant time-by-group interaction, p < 0.05. d Significant differences between groups for change at 12 weeks (unpaired t test): p < 0.01. e Significant differences between groups for change at 12 weeks (unpaired t test): p < 0.05. f Control group, n = 18 at initial measurement and 12 weeks; n = 17 at 4 and 8 weeks.

Skinfold thickness (mm)b,e Control group 27.0 ± 1.5 GTE group 27.9 ± 1.8 TFA (cm2 )b,f Control group 261.0 ± 12.7 GTE group 258.4 ± 11.0 VFA (cm2 )b,f Control group 89.3 ± 5.8 GTE group 83.1 ± 5.7 SFA (cm2 )b,c,e,f Control group 171.7 ± 10.7 GTE group 175.3 ± 8.2


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lunch, and dinner (Dulloo et al., 1999). The results showed that EGCGcontaining green tea extracts that contain caffeine are more potent than caffeine alone at stimulating 24-hour energy expenditure and fat oxidation and urinary norepinephrine excretion. However, in another study involving 104 overweight and moderately obese male and female subjects, ages of 18–60 years and BMI of 25–35 kg/m2 , the level of green tea extracts that contained caffeine (104 mg/day) and EGCG (323 mg/day) were given for 13 weeks was not associated with weight maintenance after a 7.5% body weight loss in very low energy diet subjects (Kovacs et al., 2004). This study also showed that habitual caffeine consumption affected weight maintenance in the green tea treatment. In addition, these clinical observations indicated that long-term, but not short-term, oral consumption of green tea appeared to reduce the body weight and/or fat. The difference in regulating body weight from these studies may be attributable to the protocols employed, the purity of green tea extracts, the period of administration, the percentage of the caffeine, and the physiological condition of the subjects.

Summary and Future Direction Obesity is associated with high blood cholesterol and a high risk for developing diabetes and cardiovascular diseases. Therefore, the management of body weight and obesity is increasingly recognized as a key factor to maintain healthy cholesterol profiles and to reduce cardiovascular risk. Several drugs are tested and used to treat obese-related metabolic diseases in association with the possibility of preventing body fat accumulation. Increasing interest in the health benefits of tea has led to the addition of tea extracts in dietary supplements and functional foods among these substances of interest. Especially, EGCG is known to have a beneficial effect on human health that reduced adipocyte differentiation and decreased TG levels. However, epidemiologic evidence regarding the effects of tea consumption on obesity-related disease is conflicting. This is an important area for future investigations, as it would provide further insight on precise mechanism of EGCG during adipogenesis in the patients. Although more studies are required to examine the effects and mechanisms of EGCG in animals and humans, the antiadipogenic effect of EGCG on adipocyte differentiation seems sounding and promising therapeutic treatment against obesity. Also, the various mechanisms discussed in this review could be utilized in the treatment of obesity using EGCG.


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Acknowledgments We are grateful to Dr. Dehua Cao at LMS/NIAAA/NIH for providing the information of green tea.

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CHAPTER 12

Capsaicin Astrid J.P.G. Smeets, PhD, and Prof. Dr. Margriet Westerterp-Plantenga, PhD

Abstract Capsaicin is a major pungent principle present in a variety of capsicum fruits such as hot peppers. In rats, capsaicin increases catecholamine secretion from the adrenal medulla, mainly through activation of the sympathic nervous system. As a result of β-adrenergic stimulation, capsaicin may increase in thermogenesis. In addition, animal studies showed that the administration of capsaicin favors an increase in lipid oxidation and a decrease in body fat mass. In lean human subjects, the addition of capsaicin to a meal increased diet-induced thermogenesis, increased fat oxidation, reduced hunger, and prospective food consumption before a subsequent ad libitum meal, and reduced energy, protein, and fat intake during a subsequent ad libitum meal. Capsaicin treatment, during a 3-month weight maintenance after weight-loss period, attenuated the increase in RQ and the decrease in fat oxidation compared to placebo treatment. Furthermore, tended resting EE as a function of FFM to be increased in the capsaicin group, compared with placebo. Summarized, these observations suggest that capsaicin can realistically be considered as a functional agent that could help preventing a positive energy balance and obesity.

Introduction Research has been focusing on specific food components, which may have favorable effects on weight loss, weight maintenance, and metabolism. Certain spices and herbs are used to give flavor to foods and drinks without adding calories. Moreover, consumption of spiced 201


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foods or herbal drinks may lead to greater thermogenesis and in some cases to greater satiety. Therefore, it is suggested that these ingredients can realistically be considered as functional agents that could help preventing a positive energy balance and obesity. Capsaicin (8-methyl-Nvanillyl-6-nonenamide) is a major pungent principle present in a variety of capsicum fruits such as hot peppers, which are plants belonging to the genus Capsicum (Govindarajan and Sathyanarayana, 1991). Capsaicin is widely consumed as a food additive throughout the world, particularly in South East Asian and Latin American countries. The capsaicin content of hot red peppers ranges from 0.1% to 1.0% (Govindarajan and Sathyanarayana, 1991). Capsaicin is present in large quantities in the placental tissue (which holds the seeds), the internal membranes and, to a lesser extent, the other fleshy parts of the fruits of plants in the genus Capsicum. Contrary to popular belief, the seeds themselves do not contain any capsaicin, yet the highest concentration of capsaicin can be found in the white pith around the seeds. The amount of capsaicin is often indicated by the number of Scoville heat units (SHU). A more accurate method to measure the amount of capsaicin is high-performance liquid chromatography (HPLC). This identifies and measures the heat-producing chemicals expressed in ASTA pungency units. Numerous animal studies have shown that capsaicin can increase the activity of central nervous system with a consequent stimulation of β-adrenergic receptors. In addition, animal studies showed that the administration of capsaicin favors an increase in lipid oxidation and a decrease in body fat mass. Capsaicin is perceived as a hot substance (Rolls et al., 2003). Because the ingestion of hot substances can lead to an increase in body temperature, feedback mechanisms are activated to lower body temperature, such as blood vessel dilatation and sweating. The greater heat loss, due to blood vessel dilatation and sweating, after capsaicin ingestion may contribute to higher thermogenesis. Accordingly, these observations suggest that capsaicin can realistically be considered as a functional agent that could help preventing a positive energy balance and obesity.

Efficacy In a series of human studies, Yoshioka et al. showed an increase in diet-induced thermogenesis and a decrease in respiratory quotient (RQ) immediately after a meal to which red pepper (capsaicin) was added,


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implying a shift in substrate oxidation from carbohydrate to fat oxidation (Yoshioka et al., 1995, 1998, 1999, 2001). Consumption of a breakfast with capsaicin caused an immediate increase in diet-induced energy expenditure in Japanese males (Yoshioka et al., 1995). This increase was caused by β-adrenergic stimulation since β-adrenergic blockade abolished this increase in diet-induced energy expenditure (Yoshioka et al., 1995, 2001). In 13 Japanese female subjects, addition of red pepper to the experimental meals increased postprandial energy expenditure and lipid oxidation as well (Yoshioka et al., 1998). These subjects were submitted to the four following experimental conditions at breakfast time: (1) High-fat meal; (2) High-fat meal + red pepper; (3) High-carbohydrate meal; (4) High-carbohydrate meal + red pepper. The results showed that red pepper supplementation increased both postprandial diet-induced thermogenesis and lipid oxidation. Interestingly, this stimulating effect was more pronounced after the high-fat breakfast (Fig. 12.1). Belza et al. studied the thermogenic effect of a combination of capsaicin, green tea extract (catechins and caffeine), tyrosine, and calcium after a 7-day treatment (Belza and Jessen, 2005). Energy expenditure was increased by 160 kJ/day by the combination of combination of capsaicin, green tea extract (catechins and caffeine), tyrosine, and calcium as compared to placebo, whereas the enterocoated preparation of the combined bioactive components had no such effect. The lack of effect of the enterocoated preparation suggests that a local action of capsaicin in the gastric mucosa is a prerequisite for exerting the thermogenic effect. Additionally, the effects of capsaicin on feeding behaviors and subsequent food consumption have been studied. Red pepper ingested in a standardized meal test was found to reduce hunger level and prospective food consumption before a subsequent ad libitum meal. Moreover, the results showed that protein and fat intake was decreased during this subsequent ad libitum meal (Yoshioka et al., 1999). In a second study, Yoshioka et al. served an isocaloric appetizer, containing a sauce with or without red pepper, which was followed by an ad libitum meal and a snack several hours later (Yoshioka et al., 1999). Total energy intake was significantly lower after the ingestion of the standardized appetizer. In addition, the results of this study showed that there was a significant negative association between energy intake and the change in low-frequency/highfrequency heart interval ratio, which indicates that capsaicin can increase SNS activity. Furthermore, red pepper in combination with caffeine consumption significantly reduced the cumulative ad libitum energy intake and increases energy expenditure over 24 hours in eight Caucasian male


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Lipid oxidation (mg/min)

(a) 100

75

50

25

0

(b)

Diet composition effect Diet composition × time interaction RP effect RP × time interaction

Meal 30

0

60 90 120 150 Time after meal ingestion (min)

180

210

6 A

∆ Lipid oxidation (g)

5 B 4

BC C

3 2 1 0

HF HF-RP HC HC-RP

Figure 12.1. (a) Lipid oxidation measured for 210 minutes following ingestion of experimental meals: (···◦···), high fat; (···•···), high fat plus red pepper (RP); (-ρ-), high carbohydrate; (-π-), high carbohydrate plus RP. Values are mean for 13 subjects, with their standard errors represented by vertical bars. Three-way ANOVA revealed that postprandial lipid oxidation was significantly modified by time, diet composition, RP, diet composition × time interaction, and RP × time interaction. (b) Change in lipid oxidation following high-fat (HF) and highcarbohydrate (HC) meals with and without RP. Values are means for 13 subjects, with their standard errors represented by vertical bars. A, B, C mean values not sharing a common letter were significantly different, p < 0.05. (After Yoshioka et al., 1998).


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15

24 EI MJ/day

* #

*

10

* #

* 24-h EI Capsaicin juice 24-h EI placebo juice

5

24-h EI Capsaicin capsule 24-h EI placebo capsule

0 Men

Women

Figure 12.2. Average daily energy intake over 2 days (MJ/day) in men and women (n = 24; 35 ± 10 years; BMI: 25.0 ± 2.4 kg/m2 ), with capsaicin ingestion 30 minutes before each meal, in tomato juice versus plain tomato juice or in capsules versus placebo capsules, swallowed with tomato juice. * indicates p < 0.01 (capsaicin vs. placebo). # indicates p < 0.05 (capsaicin in juice vs. capsaicin in capsule). (After Westerterp-Plantenga et al., 2005).

subjects (Yoshioka et al., 2001). Westerterp-Plantenga et al. studied the relative oral and gastrointestinal contribution to the effects of capsaicin on food intake or macronutrient selection (Westerterp-Plantenga et al., 2005). Red pepper (0.25% capsaicin; 80,000 Scoville Thermal Units) or placebo was offered in either tomato juice or two capsules, swallowed with tomato juice 30 minutes before each meal. Both oral and gastrointestinal exposure to capsaicin increased satiety and reduced energy and fat intake; however, the stronger reduction with oral exposure indicates that also a sensory effect of capsaicin plays a role (Fig. 12.2). Concerning this sensory effect, Yoshioka et al. hypothesized that the observed effects of red pepper involve a feeling of spiciness (Yoshioka et al., 2004). The subjects ingested a placebo, a moderate or a maximal tolerable dose of red pepper in a soup or in a capsule at the beginning of a meal. Red pepper lowered subsequent energy intake in a dose-dependent manner. Moreover, the maximal tolerable dose of red pepper in the soup suppressed fat intake compared with the placebo. The capsules with the maximal tolerable dose tended to decrease fat intake compared with the placebo condition; this effect was very similar to the soup with the maximal tolerable dose. Consequently, the authors suggested that the effects of red pepper on energy and macronutrient intake do not occur in the mouth.


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Further studies related to red pepper and food intake in overweight, obese, and postobese individuals will be required.

Mechanism of Actions The stimulatory effect of pungent principles such as capsaicin is likely due to the involvement of a transient receptor potential vanilloid receptor 1 (TRPV1)-linked thermogenic mechanism (Eldershaw et al., 1994). This vanilloid receptor is expressed in sensory neurons, the brain, and various nonneuronal tissues, and is also involved in the pain pathway (Caterina et al., 2000; Szallasi, 2005). Heat, protons, and vanilloids can activate the TRPV1 receptor (Szallasi, 2005). Capsaicin has been reported to increase thermogenesis by enhancing catecholamine secretion from the adrenal medulla in rats, mainly through activation of the sympathic nervous system (SNS) (Kawada et al., 1986, 1988; Watanabe et al., 1987, 1988). The increase in thermogenesis induced by capsaicin is due to β-adrenergic stimulation (Yoshioka et al., 1995). Both animal and human studies showed that the increase in thermogenesis is abolished after administration of β-adrenergic blockers such as propranolol (Kawada et al., 1986; Watanabe et al., 1988). Because of its stimulating effects on the SNS, capsaicin may influence both energy expenditure and energy intake with respect to the regulation of energy balance. Possible SNS involvement in thermogenesis is suggested by the observation that, during the infusion of nor-epinephrine or epinephrine, thermogenesis increased significantly (Kurpad et al., 1994; Simonsen et al., 1992). Furthermore, SNS activity is reciprocally related to food intake (Bray, 1993). SNS activity is diminished in obese (prone) subjects, and during negative energy balance. Capsaicin may counteract this by stimulating SNS activity.

Safety The acute toxicity of capsaicin has been determined in several animal species (Glinsukon et al., 1980). The relatively low toxicity induced by oral dosage of capsaicin appears to be associated with gastrointestinal enzyme activity. The likely mechanism of lethal effects of capsaicin has not been elucidated, but is considered to involve respiratory paralysis. A 4-week feeding study by Jang et al. revealed that diets containing 0.5–10%


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of ground capsicum fruit is relatively nontoxic at the doses tested (Jang et al., 1992). Ingestion of capsaicin in large subchronic doses has been reported to cause histopathological and biochemical changes including acute erosion of gastric mucosa and hepatic necrosis (Agrawal and Bhide, 1988; Lee, 1963; Monsereenusorn et al., 1982; Schneider et al., 1956). The long history of use as a food additive/component without any indication of deleterious health effects suggests that the potential risks to humans from both dietary and occupational exposure are negligible.

Food/Supplement Applications Capsaicin is the spicy component of hot, sweet, and bell peppers, which are plants belonging to the genus Capsicum. Commercially available capsules (range 9,000–40,000 Scoville Heat Units), often sold as “Cayenne pepper,” contain capsaicin extracts from natural sources.

Patents In addition to numerous patents on capsaicin application in the field of pain relief, several patents on the application of capsaicin in the field of obesity have been filed. Most of these patents describe the composition of a mix of compounds, including capsaicin, which is claimed to suppress appetite or stimulate metabolism.

Research Findings Weight Control Lejeune et al. tested capsaicin for its potential to facilitate weight maintenance in a postobese state. Obese individuals were subjected to either a placebo or a capsaicin (135 mg/day) treatment for 3 months after having experienced a moderate weight loss by energy restriction (Lejeune et al., 2003). During weight regain, the increase in RQ was smaller in the capsaicin group, so the decrease in fat oxidation was smaller compared with placebo. The net fat oxidation (g/h) after weight maintenance was also higher in the capsaicin group compared with placebo. Furthermore tended resting EE as a function of FFM to be increased in the capsaicin group, compared with placebo. In a recent study, Belza et al. studied the effects of a combination of tyrosine, capsaicin, catechines, and caffeine on thermogenesis and body fat loss in overweight and obese subjects (Belza et al.,


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2007). Subjects that had lost >4% of their initial weights after a 4-week hypocaloric diet were randomized to receive either placebo or bioactive supplement in a double-blind, 8-week intervention. The bioactive supplement increased thermogenesis more than placebo, and the effect was maintained after 8 weeks and accompanied by a slight reduction in body fat mass. These results suggest that capsaicin in combination with other bioactive components may support weight maintenance after a hypocaloric diet.

Food Applications Weight Control The extreme pungency of capsaicin and the possible burning feeling in the stomach may limit its intake on the long term. Therefore, capsaicin analogues with no pungency, such as CH-19 Sweet, a nonpungent cultivar of red pepper, may be an alternative. Ohnuki et al. observed that CH-19 Sweet enhanced adrenalin secretion, increased oxygen consumption, and suppressed fat accumulation in rats similarly to capsaicin (Ohnuki et al., 2001a). In humans, CH-19 Sweet increased oxygen consumption, suggesting increased thermogenesis (Inoue et al., 2007; Ohnuki et al., 2001b).

Suppliers Commercially available capsules containing capsaicin can be purchased online: www.nutraceutical.com www.nutrasanus.com www.naturesway.com

References Agrawal RC, Bhide SV. Histopathological studies on toxicity of chilli (capsaicin) in Syrian golden hamsters. Indian J Exp Bio1 1988;26:377–382. Belza A, Frandsen E, Kondrup J. Body fat loss achieved by stimulation of thermogenesis by a combination of bioactive food ingredients: a placebo-controlled, double-blind 8-week intervention in obese subjects. Int J Obes (Lond) 2007;31(1):121–130.


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Belza A, Jessen AB. Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation. Eur J Clin Nutr 2005;59(6):733–741. Bray GA. Food intake, sympathetic activity, and adrenal steroids. Brain Res Bull 1993;32:537–541. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, PetersenZeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000;288:306–313. Eldershaw TP, Colquhoun EQ, Bennett KL, Dora KA, Clark MG. Resiniferatoxin and piperine: capsaicin-like stimulators of oxygen uptake in the perfused rat hindlimb. Life Sci 1994;55:389–397. Glinsukon T, Stitmunnaithum V, Toskulkao C, Buranawuti T, Tangkrisanavinont V. Acute toxicity of capsaicin in several animal species. Toxicon 1980;18(2):215–220. Govindarajan VS, Sathyanarayana MN. Capsicum–production, technology, chemistry, and quality. Part V. Impact on physiology, pharmacology, nutrition, and metabolism; structure, pungency, pain, and desensitization sequences. CRC Crit Rev Food Sci Technol 1991;29:435–474. Inoue N, Matsunaga Y, Satoh H, Takahashi M. Enhanced energy expenditure and fat oxidation in humans with high BMI scores by the ingestion of novel and non-pungent capsaicin analogues (capsinoids). Biosci Biotechnol Biochem 2007;71(2):380–389. Jang JJ, Devor DE, Logsdon DL, Ward JM. Food Chem Toxicol 1992;3:783–787. Kawada T, Sakabe S, Watanabe T, Yamamoto M, Iwai K. Some pungent principles of spices cause the adrenal medulla to secrete catecholamine in anesthetized rats. Proc Soc Exp Biol Med 1988;188:229–233. Kawada T, Watanabe T, Takaishi T, Tanaka T, Iwai K. Capsaicin-induced beta-adrenergic action on energy metabolism in rats: influence of capsaicin on oxygen consumption, the respiratory quotient, and substrate utilization. Proc Soc Exp Biol Med 1986;183:250–256. Kurpad AV, Khan K, Calder AG, Elia M. Muscle and whole body metabolism after norepinephrine. Am J Physiol 1994;266:E877–E884. Lee SO. Korean J Intern Med 1963;6:383–395.


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Lejeune MPGM, Kovacs EMR, Westerterp-Plantenga MS. Effect of capsaicin on substrate oxidation and weight maintenance after modest body-weight loss in human subjects. Br J Nutr 2003;90:1–10. Monsereenusorn Y, Kongsamut S, Pezalla PD. Capsaicin—a literature survey. CRC Crit Rev Toxicol 1982;10:321–339. Ohnuki K, Haramizu S, Oki K, Watanabe T, Yazawa S, Fushiki T. Administration of capsiate, a non-pungent capsaicin analog, promotes energy metabolism and suppresses body fat accumulation in mice. Biosci Biotechnol Biochem 2001a;65(12):2735–2740. Ohnuki K, Niwa S, Maeda S, Inoue N, Yazawa S, Fushiki T. CH-19 sweet, a non-pungent cultivar of red pepper, increased body temperature and oxygen consumption in humans. Biosci Biotechnol Biochem 2001b;65(9):2033–2036. Rolls ET, Verhagen JV, Kadohisa M. Representations of the texture of food in the primate orbitofrontal cortex: neurons responding to viscosity, grittiness, and capsaicin. J Neurophysiol 2003;90:3711–3724. Schneider MA, Deluca V, Gray SJ. Am J Gastroenterol 1956;26:722–726. Simonsen L, Bulow J, Madsen J, Christensen NJ. Thermogenic response to epinephrine in the forearm and abdominal subcutaneous adipose tissue. Am J Physiol 1992;263:E850–E855. Szallasi A. Piperine: researchers discover new flavor in an ancient spice. Trends Pharmacol Sci 2005;26:437–479. Watanabe T, Kawada T, Kurosawa M, Sato A, Iwai K. Adrenal sympathetic efferent nerve and catecholamine secretion excitation caused by capsaicin in rats. Am J Physiol 1988;255:E23–E27. Watanabe T, Kawada T, Yamamoto M, Iwai K. Capsaicin, a pungent principle of hot red pepper, evokes catecholamine secretion from the adrenal medulla of anesthetized rats. Biochem Biophys Res Commun 1987;142:259–264. Westerterp-Plantenga MS, Smeets A, Lejeune MP. Sensory and gastrointestinal satiety effects of capsaicin on food intake. Int J Obes 2005;29:682–688. Yoshioka M, Doucet E, Drapeau V, Dionne I, Tremblay A. Combined effects of red pepper and caffeine consumption on 24 h energy balance in subjects given free access to foods. Br J Nutr 2001;85:203–211.


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Yoshioka M, Imanaga M, Ueyama H, Yamane M, Kubo Y, Boivin A, St-Amand J, Tanaka H, Kiyonaga A. Maximum tolerable dose of red pepper decreases fat intake independently of spicy sensation in the mouth. Br J Nutr 2004;91(6):991–995. Yoshioka M, Lim K, Kikuzato S, Kiyonaga A, Tanaka H, Shindo M, Suzuki M. Effects of red-pepper diet on the energy metabolism in men. J Nutr Sci Vitaminol 1995;41:647–656. Yoshioka M, St-Pierre S, Drapeau V, Dionne I, Doucet E, Suzuki M, Tremblay A. Effects of red pepper on appetite and energy intake. Br J Nutr 1999;82:115–123. Yoshioka M, St-Pierre S, Suzuki M, Tremblay A. Effects of red pepper added to high-fat and high-carbohydrate meals on energy metabolism and substrate utilization in Japanse women. Br J Nutr 1998;80:503–510.


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PART IV

Fiber based ingredients

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CHAPTER 13 R NUTRIOSE (Resistant Dextrin) in Satiety Control Susan S. Cho, PhD, and Iris L. Case, BS

Abstract r NUTRIOSE or resistant dextrin (RD) is a water-soluble polymer that is largely resistant to digestion and absorption in the small intestine, and fermented in the colon, thus meeting the classification for dietary fiber. RDs can r FB) or maize starch (RDbe made from either wheat starch (RD; NUTRIOSE r r corn; NUTRIOSE FM). NUTRIOSE is considered as GRAS (generally recognized as safe) ingredients. RDs are well tolerated at a dose of 45 g/day. It has been estimated that the small intestine digestibility of RD is 15% and that more than 75% of RD is fermented in the human gastrointestinal tract. The net energy value of RD was determined to be 2.1 kcal/g, which is in agreement with the caloric value estimated for other soluble dietary fibers. A recent study in r enhanced overweight Chinese volunteers indicated that 34 g of NUTRIOSE higher satiety as compared to a maltodextrin placebo, the result of which lowered r group over a period of the caloric intake and body weight of the NUTRIOSE 3 months. This soluble fiber is slowly digested in the small intestine that induces low glycemic and insulinemic responses. RD can be used in foods and beverages to provide desirable sensory properties as well as various health benefits such as prebiotic effects, satiety management, intestinal regularity, and glycemic control.

Introduction r NUTRIOSE is a water-soluble polymer derived from enzymatically hydrolyzed starch heated at high temperature and adjusted to a low

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moisture level in the presence of an acid catalyst (Lefranc-Millot, 2008). The dextrin obtained is purified with activated carbon and demineralized by exchange resins. Afterward, the product is chromatographed, and the r high molecular weight fraction is retained and spray dried. NUTRIOSE is resistant to digestion and absorption in the small intestine; thus, it is classified as RD. In addition to the typical starch α-1,4 and α-1,6 glucosidic linkages, the presence of α-1,2 and α-1,3 glycosidic linkages makes RDs resistant to the hydrolysis by human alimentary enzymes. Thus, the r or RD can be made from RDs are classified as dietary fiber. NUTRIOSE r r FM). either wheat starch (NUTRIOSE FB) or corn starch (NUTRIOSE r NUTRIOSE FB is a mixture of glucose polymers with degrees of polymerization in a range of 12–25 (mean 18). The number-average molecular weight is approximately 2,480 (range 2,000–4,000 Da) and the weightaverage molecular weight is about 5,344 (range 4,000–6,000 Da). RD can be used in various processed foods and beverages to provide desirable sensory properties as well as various health benefits including limited glycemic response and intestinal regularity. This soluble fiber has a very low hygroscopicity, as it maintains its free flowing, powder nature at an 80% relative humidity (24 hours, 20◦ C) before clumping occurs. RD is stable in high-temperature processing conditions, including sterilization and ultrahigh temperature treatment. RD is stable in highly acidic conditions as well as large-scale shear processes such as extrusion. RD does not significantly add viscosity to formulations and it is not readily fermented by bacterial strains typically found in milk products; thus, it can be used in dairy products designed for fiber supplementation and prebiotic effects.

Safety r NUTRIOSE and dextrins are considered as “GRAS” (Wils et al., 2008). The safety of RS was reviewed by the U.S. FDA in 1990 to be classified as dextrins (21 CFR Section 184.1444). The joint FAO/WHO Expert Committee on Food Additives (JECFA) has also recognized the safety of dextrins and has allocated an “acceptable daily intake (ADI) not specified” for white and yellow dextrins (JECFA, 1974). Data from an acute toxicity study, a 90-day feeding study, mutagenicr FB is ity tests, and human clinical trials indicate that NUTRIOSE safe and well tolerated for human use (Pasman et al., 2006; Vermorel et al., 2004; Wils et al., 2008). It was also found that RD did not affect the


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absorption and binding properties of various minerals, such as magnesium and calcium (Vermorel et al., 2004). An acute oral toxicity study with a fixed dose of 2,000 mg/kg indicated that the lethal dose (LD50 ) of RD was greater than 2,000 mg/kg (Wils et al., 2008). The 90 days feeding study revealed no treatment-related adverse effects when RD was given to rats at a level of 5% in the diet for 13 weeks (Wils et al., 2008). No mortality and no behavior modification of significance occurred during the study. No diarrhea or soft feces as well as no ophthalmological abnormalities were observed during the study. The no-observable adverse effect levels (NOAELs) were established by the highest tested doses: 4.4 g/kg body weight (BW) day in males and 6.5 g/kg BW/day in females. This low toxicity is consistent with the similar low toxicity reported for RD originated from corn starch (Okuma and Wakabayashi, 2001). An Ames test revealed that RD induced no mutagenic activity in the five Salmonella typhimurium strains tested (Wils et al., 2008). In vitro mammalian cell mutation assays at the TK locus in L5178y mouse lymphoma cells showed that there was no mutagenic potential of RD. There was no significant increase in the mean number of induced mutants at any dose tested as shown in the assays with and without metabolic activation. In addition, RD produced no significant variation in the number of large or small colony mutants relative to the solvent control with and without metabolic activation. The results of safety studies on other RDs are also relevant to those of RD. In a rat feeding experiment, the LD50 of corn-based RD was found to be over 40 g/kg BW, the maximum dosage in the acute toxicity study (Wakabayashi et al., 1992). In rats fed 10% RD (derived from corn) in water for 5 weeks, no harmful effects were observed on internal organs such as the pancreas, kidney, and liver. Furthermore, there is no evidence of mutagenicity caused by the consumption of corn-based RD (Wakabayashi et al., 1992). Corn-based RD was found to have no adverse effects on mineral metabolism as measured by mineral binding properties in an in vitro experiment (Nomura et al., 1992). The demonstrated safety data on r FB and other types of RDs are mutually supportive. NUTRIOSE

Safety Studies in Humans Various researchers reported that RD was well tolerated up to 45 g a day in both short term (van den Heuvel et al., 2005) and longer term (Pasman et al., 2006), with no negative effects found for gastrointestinal


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parameters. At the end of the study, there was no significant difference in gastrointestinal complaints for the different treatments. This indicates that after 4–5 weeks consumption, habituation to the dose of RD had likely occurred (Pasman et al., 2006). High daily dosages of 60 and 80 g caused mild bloating and increased flatulence in some subjects, but no diarrhea was reported (van den Heuvel et al., 2005, 2005). Compared with a placebo, flatulence occurred more frequently over the 7-day period when 30, 60, or 80 g/day of RD was tested (p < 0.05). On days 6–7, 60 and 80 g/day of RD produced a high frequency of flatulence and bloating (p < 0.05), and 60 g RD decreased the frequency of defecation (p < 0.05). None of the doses of RD resulted in diarrhea.

Digestibility Pasman et al. (2006) reported a small intestine digestibility of 15%, with the range of 8.7–19%, for this RD. More than 87% of RD is considered to be digested or fermented in the human gastrointestinal tract (van den Heuvel et al., 2005). van den Heuvel et al. (2005) reported that the fecal residue of RD nonlinearly increased with the dose. In this study, it was calculated that about 2% of 10 g/day RD and 13% of 80 g/day RD were recovered in the feces, assuming a constant excretion of RD in feces per 24 hours (van den Heuvel et al., 2005). Vermorel et al. (2004) estimated that the apparent digestibility of the RD was 90.8% and that approximately 76% of the RD was fermented. A daily dose of over 30 g of RD increased the concentration of αglucosidase. The α-glucosidase activity, whose activity has been shown to improve the fermentation of RD leading to short-chain fatty acids (SCFAs) and lactic acids that are a source of energy for tissues. A daily dose of over 10 g RD/day increased β-glucosidase activity in a dose-dependent manner. An increase in β-glucosidase may be beneficial for health by releasing flavonoids, which are known to promote antioxidative, anticarcinogenic, and immune stimulatory effects (Wollowski et al., 2000). Rat and in vitro experiments indicate that only 85% of RD reaches the colon (Vermorel et al., 2004), where it is fermented by the bacterial flora. RD recovered in feces as polymerized glucose represented the nondigested and nonfermented part of RD. Supplementation of RD increased wet and dry stool outputs by 45% and 70%, respectively (Vermorel et al., 2004), probably due to increased dry matter (DM) output (38%) and increased water output (62%). However, van den Heuvel et al. (2005) reported that


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supplementation with 10–15 g of RD decreased wet and dry weight of feces without changing the percentage DM. Thicker feces were observed during the past 24 hours on 15 g/day of RD as the amount of fecal water probably decreased. A decreased level of fecal water may be due to high SCFAs absorption that often accompanies high water and salt absorption. The fecal pH in RD-treated groups was decreased from 6.6 (day 1) to 6.1 (day 35), indicating increased fermentation while the placebo group maintained a pH range of 6.5–6.6 during the test period (Vermorel et al., 2004). The pH remained stable from day 21 onward for all groups. The total sum of the SCFAs (acetate, propionate, butyrate, and isoforms of SCFAs) did not show changes in concentration due to time or study substance.

Fermentation The colonic effects and the production of SCFAs, as contributors to the daily energy supply, are key factors in providing a long-lasting energy supply of RD. van den Heuvel et al. (2005) studied the fermentation of RD by a breath hydrogen excretion test. This test was carried out on the last day of 10 or 15 g/day of RD or placebo treatment. As compared with the baseline, breath hydrogen excretion levels before breakfast significantly increased. However, there was no overall difference between the areas under the curve (AUC) among treatments, except from the points 270 and 300 minutes after ingestion. The absence of an overall significant difference in AUC attributable to RD may be due to a relatively small dose of RD (2.5 or 3.0 g) in each meal and/or the large variations in measurement data.

Caloric Value Direct determination of net energy value (NEV) of fibers is difficult, mainly because they are consumed in small quantities, and thus induce small differences in energy expenditure. Digestible energy value (DEV), metabolizable energy value (MEV), and NEV are generally estimated from measurements of fiber fermentability, breath tests, and hypotheses on gas, microbial mass and volatile fatty acids (VFAs) production, and efficiency of VFA energy utilization. In the study of Vermorel et al. (2004), the NEV of the tested RD was estimated using three prediction equations as outlined in Livesey (1992, 2001). First, the MEV of the tested RD was estimated from its


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metabolizable energy content, assuming that hydrogen and methane energy losses accounted for 5% of the fermented carbohydrate (CHO) energy, and fermentation heat also accounted for 5%. VFA energy was estimated as “Estimated ME Glucose energy (GE)” (derived from enzymatic digestion). The efficiencies of GE and VFA energy utilization are estimated at 1 and 0.85, respectively, to produce Equation (1). NEV = (Gross energy × Enzymatic digestibility (ED)) +(VFA energy × 0.85)

(13.1)

Secondly, the carbohydrate substitutes method was used: The enzymatically digested fraction is assumed to produce glucose used with an energetic efficiency of 1. Fermentable carbohydrates are assumed to supply 8 kJ NE/g to result in Equation (2). NEV = (Gross energy × Enzymatic digestibility) +(Fermentable CHO × 8)

(13.2)

Third is the minimal methodology for net ME. The apparent digestibility of fermentable carbohydrates is used to estimate VFA production, assuming that 65% of actually “fermented energy” is recovered as VFA. The efficiency of ME utilization from fermentable carbohydrates is assumed to be 0.76 to yield Equation (3). NEV = (GE × ED) + (Fermentable CHO ×Unavailable CHO digestibility × 0.65 × 0.76) (13.3) From these three methods, NEVs of RD were estimated to be 8.7, 8.9, and 11.4 kJ/g DM in healthy young men (Vermorel et al., 2004). In this study, ten healthy young men were fed for 31-day period a maintenance r diet supplemented with either placebo (dextrose) or the NUTRIOSE (100 g DM/day) in a crossover design. After a 20-day adaptation period, food intake was determined for 11 days using the duplicate meal method, and feces and urine were collected for 10 days for further analyses. The r was 14.1 (SD 2.3) kJ/g DM, 14% less ME value of the NUTRIOSE than the tabulated values of sucrose and starch. NEV of RD (mean of 2.0 kcal/g) estimated by Vermorel et al. (2004) is in agreement with the caloric value estimated for soluble dietary fibers (Livesey, 1992). These studies indicate that soluble dietary fibers may have a positive impact on the total daily energy expenditures through the colonic fermentations and the viscosity of the gut contents. Moreover, RD, used as a bulking agent to easily replace fat or carbohydrates, allows obtaining food with lower overall caloric value.


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Satiety During and immediately after eating, afferent information provides the major control over appetite (Blundell, 1999). Physiological events are indeed triggered in responses to the ingestion of food and form the inhibitory processes which stop eating and then prevent the reoccurrence of eating until another meal is triggered. These physiological events are termed “satiety signals”. Satiation is the process that leads to the termination of food intake. Termination of the period of satiety leads to the resurgence of the feeling of hunger and a consequent resumption of the food-intake cycle (Blundell, 1999). It appears that RD has a more powerful satiating effect in subjects as compared to a maltodextrin placebo. During a recent study, with no energy restriction (ad libitum diet) but in which energy intakes were recorded, overweight Chinese volunteers r or 17 g malreceived beverages containing either 17 g NUTRIOSE todextrin (placebo), twice daily, for 12 weeks. It was observed that 34 g of RD enhanced higher satiety than did maltodextrin (Roquette Group, 2008). In this study, significant decreases in body weight (p < 0.0001), body mass index (p < 0.0001), body fat (p < 0.0001), and hunger (p < 0.001) associated with a decrease in caloric intake (p < 0.001) were measured throughout the study in the RD group. Abdominal scans indicated a significant reduction of waist circumference in the RD group while no changes were observed in the placebo group (p < 0.001). The authors concluded that RD supplementation significantly decreased the feeling of hunger and expression of some biological markers of metabolic syndrome, including body weight than did maltodextrin. van den Heuvel et al. (2005) also investigated the effects of RD supplementation to usual diets, meals contained similar amounts of energy to their habitual breakfast or dinner, on satiety and energy intakes. In this study, subjects (average BMI = 22.3 kg/m2 ) ate standard breakfast, lunch, and afternoon snacks that were not designed for energy restriction. Hunger and satiety were measured just before breakfast (time point 0) and at 30, 60, 90, 120, 150, 180, 240 (just before lunch), 270, and 480 minutes. Feelings of hunger and satiety were rated by a 10 cm visual analogue scale (VAS), such as appetite for a meal, appetite for something sweet, appetite for something savory, satiety (fullness), and feeble/weak with hunger) on day 7 of treatment. Only the AUC of the rating on “feeble or weak with hunger” was lower on day 7 of the treatment with 15 g/day of RD compared to 15 g/day of the placebo (p = 0.04). No other significant differences in satiety scores were found. Also, an increasing dose of RD did not affect food habits as compared with the placebo. The findings from


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these studies suggest that RD may have a satiating effect in subjects with energy-unrestricted diets.

Body Fat Control in Animals It has been proposed that RD reduced the body fat content in animals by moderating postprandial glucose levels and by lowering insulin secretion (Okuma and Wakabayashi, 2001). Wakabayashi et al. (1991) reported that RD (5%) supplementation to a high-sucrose diet for 8 weeks did not induce an increase in body fat, whereas a high-sucrose diet alone increased the body fat in rats. A 110-day-old broiler chicken study reported a similar trend (Wakanabe et al., 1993). Supplementation of 5% RD-corn to a diet reduced the total body fat content, the fat content in the liver (from 27% to 17%) and other internal organs in broiler chickens.

Glycemic Response and Satiety The rate of absorption of the RD at the different stages of the gastrointestinal tract plays a major role in determining its metabolic effect. This soluble fiber is slowly digested in the small intestine (15% of the ingested dose evaluated in vitro; Vermorel et al., 2004), which induces a low glycemic response (GR = 25) and a low insulinemic response (IR = 13) (Donazzolo et al., 2003). As compared to glucose, the low insulinemic response of the RD contributes to a greater feeling of satiety. Incorporation of this RD into foods such as pasta, biscuits, and syrups significantly reduced the glycemic response of a meal (Lefranc-Millot, 2008; Lefranc-Millot et al., 2006). Peak glycemia was 7.6 mmol/L for glucose and 5.3 mmol for the pasta containing RD. Mean AUC for RD pasta was significantly lower than that of glucose (42.0 vs. 123.6, p < 0.01). Syrups made with RD elicit a glucose response of only 10% of the equivalent product made with sugar when used in a fruit drink (Lefranc-Millot et al., 2006). Mean AUC for RD biscuits was significantly lower than that of glucose (66.6 vs. 137.0, p < 0.01). Several researchers have reported that low glycemic index (GI) foods enhance higher satiety responses than high glycemic foods. GI corresponds to the incremental area under the blood response curve measured over 2-hour time of a 50-g CHO portion of a test food expressed as percentage of the response to the same amount of CHO from a reference food (usually glucose) consumed by the same subject (FAO/WHO, 1988). Because lowGI foods are characterized by a slower rate of digestion and absorption,


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prolonged feedback (likely through satiety signals) to the hunger/satiety center in the brain is probably due to continuous stimulation of nutrient receptors in the gastrointestinal tract. In a study with 26 males (mean BMI = 23.4 ± 2.2 kg/m2 ), Pasman et al. (2003) reported that consumption of a simple CHO breakfast resulted in higher glucose and insulin levels at 30 minutes after breakfast consumption. Satiety scores were higher after complex CHO breakfast consumption for the first 90 minutes after intake. Warren et al. (2003) reported that low-GI foods eaten at breakfast have a significant impact on food intake at lunch. This study investigated the effect of three test breakfasts—low-GI, low-GI with 10% added sucrose, and high-GI—on ad libitum lunch intake, appetite, and satiety. Lunch intake was lower after low-GI and low-GI with added sucrose breakfasts compared with lunch intake after high-GI and habitual breakfasts (which were high-GI): highGI versus low-GI = 145 ± 54 kcal; high-GI versus low-GI plus sucrose = 119 ± 53 kcal; low-GI plus sucrose versus low-GI = 27 ± 54 kcal. Lunch intake after the low-GI breakfast and the low-GI breakfast with added sucrose was also significantly lower than that after the habitual breakfast: low-GI versus habitual = −109 ± 75 kcal; low-GI plus sucrose versus habitual = −83 ± 75 kcal; high-GI versus habitual = 36 ± 75 kcal. At lunchtime, hunger ratings were greater after the high-GI breakfast compared with the other two test breakfasts on two of the three experimental days. Prelunch satiety scales were inversely related to subsequent food intake. Based on time to request additional food, a prolongation of satiety was observed after the low-GI meal replacement as compared to high-GI meal replacement (Ball et al., 2003). There are reports that both high-GI and low-GI carbohydrates were shown to suppress appetite and food intake but the time courses were different (Anderson et al., 2002; Rogers and Blundell, 1989; Woodend and Anderson, 2001). High-GI carbohydrates induced an early short-term satiating effect. There was an inverse association between the blood glucose response and the subjective appetite and food intake in the 1 hour after consumption of isovolumetric preloads of carbohydrates (Anderson et al., 2002). One hour after their consumption, high-GI carbohydrates (glucose, polycose, and sucrose) more effectively suppressed food intake than did low-GI carbohydrates (amylose, amylopectin, and a fructose–glucose mixture). The early satiating effect of high-GI carbohydrates was also confirmed by other investigators (Rogers and Blundell, 1989; Woodend and Anderson, 2001). However, low-GI foods showed higher satiety than did high-GI foods at 2–6 hours after the ingestion (Anderson et al., 2002).


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Summary r NUTRIOSE is a soluble fiber, derived from corn or wheat, that is r can function as a bulking agent and is well classified as RD. Nutriose tolerated in humans, with a dose of 45g/day showing no side effects. Studies show that RD reduces glycemic and insulinemic responses, which is associated with satiety control. Recent studies indicate that dietary supplementation of RD may aid in satiety control. Several clinical studies have demonstrated the prebiotic nature of RD. RDs can be used in food formulations targeting satiety management. In addition, RD can be used in functional foods designed for limiting glycemic and insulinemic responses, fortifying diets in fiber, prebiotic effects, or intestinal regularity.

References Anderson GH, Catherine NL, Woodend DM. Inverse association between the effect of carbohydrates on blood glucose and subsequent short-term food intake in young men. Am J Clin Nutr 2002;76:1023–1030. Ball SD, Keller KR, Moyer-Mileur LJ. Prolongation of satiety after low versus moderately high glycemic index meals in obese adolescents. Pediatrics 2003;111(3):488–494. Blundell JE. The control of appetite: basic concepts and practical implications. Schweiz Med Wochenschr 1999;129:182–188. Donazzolo Y, Pelletier X, Cristiani I, Wils D. Glycemic and insulinemic r FB in healthy subjects. Proceedings of the indexes of NUTRIOSE Dietary Fibre Conference. Noordwijkerhout, The Netherlands, 2003, p. 53. FAO/WHO. Carbohydrates in human nutrition. Report of a Joint FAO/WHO Expert Consultation (Rome, 14–18 April 1997). FAO Food and Nutrition Paper 66. 1988. JECFA Joint Expert Committee of Food Additives (JECFA) Dextrins (WHO Food Additive Series 17). 1974. r 06: a useful soluble dietary fibre for added Lefranc-Millot C. NUTRIOSE nutritional value. Nutr Bull 2008;33:234–239.

Lefranc-Millot C, Wils D, Henry J, Lightowler H, Saniez-Degrave M-H. r r , a sugar alcohol, NUTRIOSE a resistant dextrin, and MALTISORB


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Wakabayashi S, Satouchi M, Nogami Y, Ohkuma K, Matsuoka A. Effect of indigestible dextrin on cholesterol metabolism in rat. J Jpn Soc Nutr Food Sci 1991;44:471–478 (in Japanese). Wakabayashi S, Satouchi M, Ueda Y, Ohkuma K. Acute toxicity and mutagenicity studies of indigestible dextrin, and its effect on bowel movement of the rat. J Food Hyg Soc Japan 1992;33:557–562 (in Japanese). Wakanabe O, Fujinaka K, Uchiyama K, Katta Y, Okuma K. Effects of galacto-oligosaccharides and indigestible dextrin on fat accumulation in broiler. Jpn J Poult Sci 1993;30:35 (in Japanese). Warren JM, Henry CJ, Simonite V. Low glycemic index breakfasts and reduced food intake in preadolescent children. Pediatrics 2003;112(5):e414. Wils D, Scheuplein RJ, Deremaux L, Looten P. Safety profile of a food dextrin: acute oral, 90-day rat feeding and mutagenicity studies. Food Chem Toxicol 2008;46:3254–3261. Wollowski I, Rechkemmer G, Pool-Zobel BL. Protective role of probiotics and prebiotics in colon cancer. Am J Clin Nutr 2000;73:451S–455S. Woodend DM, Anderson GH. Effect of sucrose and safflower oil preloads on short term appetite and food intake of young men. Appetite 2001;37(3):185–195.


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CHAPTER 14

Fiber and Satiety Susan S. Cho, PhD, Iris L. Case, BS, and Stephanie Nishi, BS

Abstract Dietary fiber has received much support from leading scientific authorities for the role it plays in satiety control. The USDA Dietary Guidelines for Americans state that high fiber content of foods, in particular whole grains, helps “you feel full with less calories.” The National Academy of Sciences Food and Nutrition Board also recognizes the satiety benefits of dietary fiber stating that high-fiber diets delay stomach emptying, which increases the amount of time for energy and nutrients to get absorbed from the digestive tract. Fibers tend to show good correlation to satiety but results are variable most likely due to the diverse physicochemical and gastrointestinal transit behavior of these materials. This chapter reviews the most relevant satiety clinical studies with a focus on fibers and hydrocolloids. This chapter will also address the definitions of satiation and satiety, clinical methods for measuring satiety, and physiological mechanisms of appetite regulation and control of food intakes.

Definition of Satiation and Satiety Satiation and satiety are often confused as the same physiological response, but they are in fact distinctly different phases of appetite regulation. The distinction between satiation and satiety is important to fully appreciate the key positive and negative processes based on palatability that drive food intake (appetite), and secondarily a negative feedback loop 227


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coming mainly from the gastrointestinal tract that triggers the body to stop eating. Satiation is the response to food during the course of eating and eventually brings the period of eating to an end (Stubbs et al., 1995); it represents the point where negative feedback equals positive feedback. Satiation is generally defined by the quantitation of the eating episode, that is, volume, weight, or caloric intake of food associated with a specific meal. Hunger declines as satiation develops and usually reaches its lowest point at the end of a meal. Satiety, on the other hand, is a more indirect physiological response (a negative feedback process) and is much longer in duration than satiation. Technically, it is defined as the state in which further eating is inhibited; it arises as a consequence of food ingestion and follows the end of an eating episode. The intensity of satiety is measured by the duration of time that elapses until eating is recommenced, or by the amount consumed at the next meal.

Clinical Methods for Satiety Measurements Although there is no universally standardized methodology for satiety testing, most studies either use subjective visual analogue scale (VAS) scores, direct measurements of food intake, or a combination of both. Typically, these studies present one of several test meals of varying nutrient content to each subject on several occasions (Porrini et al., 1995). At certain time points following the consumption of the test meals, subjective satiety ratings are measured repeatedly. Most of these subjective tests employ VAS scores that are usually 100 or 150 mm in length, to assess hunger, satiety, fullness, prospective food consumption, and palatability of the meals. Subjects are asked the questions, such as “how hungry do you feel?” “how satisfied do you feel?”, “how full do you feel?”, “how much do you think you can eat?”, and so on (Willis et al., 2009). When food-intake metrics are required, test subjects are given free access to food and are instructed to eat until they feel comfortably full. Food intakes (FI) and/or energy intakes (EI) are then assessed. The timing of these ad libitum food intakes vary from 1 to 8 hours post preload, but certain studies have monitored food intake well into the next day (Nilsson et al., 2008). The majority of these investigations used a crossover design where subjects received both test meals on separate occasions and thus acted as their own control. In some experiments, plasma concentrations of glucose, lactate, and satiety related gut hormones were determined concomitantly. Covert manipulation assessed the physiological effects of nutrients or foods. Volume and differences between preloads should not be apparent


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229

(Stubbs, 1999; Stubbs et al., 1995). Overt manipulation assesses interaction of and differences between preloads. Thus, differences between preloads should be apparent through labeling and sensory properties, and so on. In addition to subjective measures of satiety and food or EI, gastric emptying (GE) has been used to predict satiety. From a practical perspective, satiety and FI appear to be the most relevant measures of satiety. Since FI metrics is a direct measurement, it is generally more reliable than the subjective VAS scoring.

Regulation of Satiety and FI by the Central Nervous System Food intake (FI) is regulated mainly by the central nervous system. Due to the complexity of feeding behavior, many areas of the brain are involved in regulation of FI (Heijboer et al., 2006). The hypothalamus consists of several areas that play a role in regulating FI including the arcuate nucleus, the paraventricular nucleus, the lateral hypothalamic area, the ventromedial nucleus, and the dorsomedial nucleus. The arcuate nucleus is very important for food regulation; it contains neural circuits that receive and integrate cues pertaining to the body’s nutritional status (López et al., 2007b). The arcuate neurons then modulate other hypothalamic nuclei to adapt the body’s behavior and metabolism to the specific environmental conditions. The arcuate nucleus of the hypothalamus produces both orexigenic peptides (agouti-related protein and neuropeptide Y) and anorectic peptides (α-melanocyte-stimulating hormone and cocaine- and amphetaminerelated transcript) (Dhillo, 2007). The lateral hypothalamus also produces orexigenic peptides (melanin-concentrating hormone and orexins). Other hypothalamic factors implicated in appetite regulation include the endocannabinoids, brain-derived neurotrophic factor, nesfatin-1, AMPactivated protein kinase, mammalian target of rapamycin protein, and protein tyrosine phosphatase (Dhillo, 2007). These circulating factors affect FI by signaling to the hypothalamus and/or brainstem; signals from neurons, hormones, and nutrients are sensed by neuronal systems and influence the individual’s level of satiety (Heijboer et al., 2006; Stubbs, 1999).

Short-Term FI The hypothalamus regulates both long-term and short-term intake (Anderson et al., 2006). Gastrointestinal responses to food ingestion


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activate many of the regulation signals. These signals are transmitted to feeding centers in the brain, primarily via the vagus nerve resulting in a short-term decrease in FI. Regulation of short-term FI is dictated mainly by food signals arising from both preabsorptive action in the gut and postabsorptive metabolism. 1. Preabsorptive signals: The ingestion of food and the passage of the subsequent digestive products through the gastrointestinal tract prior to absorption produces signals that are integrated with long-term energy signals to control FI (Anderson et al., 2006). Nutrients stimulate the release of gastrointestinal hormones that act directly on receptors in the vagus nerve and in the brain. Mechanoreceptors, osmoreceptors, and chemoreceptors in the stomach and the small intestine are involved in this process. a. Ileal brake: Under normal physiological situations, undigested nutrients can reach the ileum. When this occurs, the ileum slows distal movement of luminal contents. This phenomenon has been termed “ileal brake” (Dobson et al., 1999). This brake mechanism ensures that the transit of the undigested nutrients through the rest of the ileum is slowed to optimize nutrient digestion and absorption. The ileal brake mechanism has been shown to reduce FI and increase satiety levels. Glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) are known to be ileal brake activators. b. Gastric emptying: Slower GE is associated with increased satiety (Slavin and Green, 2007). Many factors contribute to the rate of GE of a meal, including the physical state, temperature, volume, osmolality, caloric content of the meal, and hormonal interactions. Solid foods are emptied more slowly from the stomach than are liquid; increased volume accelerates the initial rate of GE, and solutions of high osmolality slow GE. Several hormones affect GE; for example, GE is slowed by GLP-1 (Anderson et al., 2006). 2. Postabsorptive signals: Digested nutrients in circulation stimulate satiety centers in the brain by endocrine and metabolic actions to generate postabsorptive satiety signals (Anderson et al., 2006). These signals could inform the brain about the nutritional status and elicit adaptive homeostatic changes in energy intake and expenditure. About 70 years ago, it was proposed that the central nervous system sensed circulating levels of metabolites such as glucose, lipids, and amino acids, and modified feeding behavior according to the levels of those molecules. This proposal has led to the formulation of the glucostatic, lipostatic, and aminostatic hypotheses (López et al., 2007a).


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3. Gut hormones related to satiety: The gut is a source of numerous peptides that contribute to the regulation of satiety, FI, and overall nutrient metabolism. After food is consumed, the digestion and absorption of nutrients are associated with increased secretion of multiple gut peptide hormones that act on distant target sites to promote the efficient uptake and storage of energy (Drucker, 2007). These peptide hormones are synthesized by enteroendocrine cells located in the epithelium of the stomach, small bowel, and large bowel and are maintained at low basal levels in the fasting state (Drucker, 2007). Gut hormones activate neural circuits, primarily the vagus nerve and hypothalamus, which communicate with peripheral organs, including the liver, muscle tissue, adipose tissue, and islets of Langerhans in the pancreas, to coordinate overall EI and assimilation. GLP-1 is a 30-amino-acid hormone that is released from L cells in the intestinal mucosa after ingestion of food (Meier and Nauck, 2005). Sustained GLP-1 receptor activation is associated with satiety and weight loss. GLP-1 is secreted within minutes of nutrient ingestion and inhibits gastrointestinal motility and secretion, acting as part of the “ileal brake” mechanism. GLP-1 is also involved in the slowing of GE and potentiating all steps of insulin biosynthesis (Meier and Nauck, 2005). Thus, GLP-1 has a critical role in FI and glycemic control (Huda et al., 2006). Decreased GLP-1 secretion is observed in subjects with type 2 diabetes, suggesting that GLP-1 may play a role in the pathogenesis or control of type 2 diabetes. Exercise has been shown to increase the acute GLP-1 response to a liquid meal (from 52% to 78%; p = 0.02) in adolescents (Chanoine et al., 2008). Fasting GLP-1 concentrations and postprandial GLP-1 responses were lower in overweight adolescents, compared to normal-weight adolescents (Chanoine et al., 2008). PYY, a 36-amino-acid peptide, is secreted primarily by the L cells in the intestinal mucosa of the ileum and large intestine (Ueno et al., 2008). Release of PYY is influenced by calorie intake as well as meal composition. Higher plasma concentrations are seen following isocaloric meals of fat compared with meals of protein or carbohydrate. In animal studies, PYY release is also stimulated by gastric acid and cholecystokinin (CCK) secretion, and by infusion of bile acids into the ileum or colon. PYY is released into the circulation in response to FI, rising to a plateau 1–2 hours after food ingestion and remaining elevated for up to 6 hours. When the presence of nutrients in the distal small intestine stimulates PYY secretion, motility and secretion are slowed in the upper small intestine, an action that contributes to the “ileal brake.” Repeated administration


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of PYY (3–36) reduces appetite, EI, and body weight in both humans and animals. PYY may have a physiological role in eating behavior, in particular in mediating the satiating effects of dietary protein (Coll et al., 2007). PYY is also involved in regulating insulin secretion and glucose homeostasis. There are reports that fasting and postprandial PYY levels are decreased in obese subjects (Grudell and Camilleri, 2007) and that overweight subjects have a relative deficiency of postprandial PYY release that is associated with reduced satiety (Coll et al., 2007). Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone (Cummings, 2006). The octanoylated 28-amino-acid peptide is produced and secreted by cells within the oxyntic glands of the stomach (Coll et al., 2007). Ghrelin mRNA expression and peptide secretion are increased by weight loss, fasting, and insulin-induced hypoglycemia (Coll et al., 2007). Peripheral administration of ghrelin stimulates appetite, FI, and decreases fat utilization. Compared to other macronutrients, the ingestion of lipids suppresses ghrelin poorly. Cholecystokinin is released from the gastrointestinal tract by the local action of digested food (Beglinger and Degen, 2004). Cholecystokinin functions as a positive feedback signal to stimulate digestive processes and as a negative feedback signal to limit the amount of food consumed during an individual meal (Beglinger and Degen, 2004). Cholecystokinin was shown to induce satiety by interacting through CCK-1 receptors located in specialized regions of the hindbrain (Chandra and Liddle, 2007).

Long-Term FI The adiposity-related hormones, such as leptin, ghrelin, and insulin have been recognized as having a major influence on mediating the longterm regulation of FI (Coll et al., 2007). Leptin enters the central nervous system by crossing the blood–brain barrier and binding to hypothalamic leptin receptors and thus acts to suppress FI (Klok et al., 2006). Conversely, ghrelin crosses the blood–brain barrier and stimulates FI by acting on several classical body weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Insulin affects neuropeptides in the hypothalamus involved in regulating FI and energy expenditure (Heijboer et al., 2006). 4. Other physiological factors affecting satiety: Aging is associated with a physiological decline in FI (Morley, 2001), which involves both peripheral and central mechanisms. Altered hedonic qualities of food


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occur due to alterations in taste and smell that accompany aging. A decline in adaptive relaxation of the fundus of the stomach and an increased rate of antral filling appear to play a role in the early satiation seen in many older persons. Cholecystokinin levels are increased with aging and older persons are more sensitive to the satiating effects of this gut hormone (Morley, 2001). The decline in testosterone levels in aging males leads to increased leptin levels, which may lead to a greater decline in FI in the older male.

Mechanism of Dietary Fiber Actions Pereira and Ludwig (2001) summarized physiologic mechanisms by which dietary fiber affects satiety and body weight regulation. Three main factors, intrinsic, hormonal, and colonic effects of dietary fiber, satiation and/or satiety. First, soluble, viscous fibers delay GE by forming a gel matrix (Howarth et al., 2001). Delayed GE increases the time permitted for absorption of energy and nutrients from the digestive tract (IOM, 2002), which in turn promotes a feeling of fullness and delayed return of appetite. Second, there is evidence that the effect of fermentable dietary fibers on satiety may be mediated through the colonic production of short-chain fatty acids (SCFA) (Hamer et al., 2008). It has also been hypothesized that SCFA produced in the large intestine can influence upper gut motility and satiety (Cherbut, 2003). Butyrate has been shown to increase the expression of PYY and proglucagon in vitro in rat epithelial cells, as well as increase PYY release, but not the expression of GLP-1, in the isolated colon of animals (Cherbut et al., 1998; Longo et al., 1991). Enteroendocrine L cells containing PYY in the human large intestine express the SCFA receptor, GPR43. Thus, activation of the SCFA receptor GPR43 may play a role in this effect on satiety (Karaki et al., 2008). However, human evidence remains limited and most evidence originates from rat studies (Hamer et al. 2008). Finally, fiber increases chewing, which limits intake by promoting the secretion of saliva and gastric juice. This results in an expansion of the stomach and increased satiety (Howarth et al., 2001). In addition, dietary fibers alter the response and actions of gut hormones such as GLP-1 and CCK. Howarth et al. (2001) and Pereira and Ludwig (2001) summarized the effects of dietary fiber on hunger, satiety, energy intake, and body weight. Most studies with controlled energy intake have reported an increase in


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satiety after meals and a decrease in subsequent hunger with an increased dietary fiber diet or meal. Studies with ad libitum energy intake indicated that an additional 14 g/day of fiber resulted in an average of 10% decrease in energy intake and an average weight loss greater than 1.9 kg following approximately 3.8 months of intervention. The effects of increasing dietary fiber were more notable in obese individuals (Pereira and Ludwig, 2001; Slavin, 2005; Slavin and Green, 2007). Many dietary fibers promote satiety and decrease FI; however, not all fibers are equivalent in this regard given the extreme variance in viscosity, solubility in the gut, fermentation profiles, and hormonal responses. Soluble and fermentable fibers such as psyllium, pectin, alginate, guar gum, and barley fibers represent a diverse class of hydrocolloids that enhance satiety presumably due to gastric thickening effects that subsequently delay emptying (Adam and Westerterp-Plantenga, 2005a, 2005b; Delargy et al., 1997; Nilsson et al., 2008). On the other hand, fibers with low viscosities, such as soy fiber and oat hull fiber, showed no effect on satiety (Bouin et al., 2001; Weickert et al., 2005, 2006b).

Authoritative Statements Related to Fiber and Satiety The most current edition of the Dietary Guidelines for Americans (USDA, 2005) reported that high fiber content of foods was inversely associated with weight gain and/or body mass index (BMI). Other scientific bodies have issued several authoritative statements as follows: Foods low in fat and high in naturally occurring fiber appear to induce satiety in humans at lower levels of caloric intake than do high fat, low fiber foods. (Surgeon General’s Report, 1988) Overweight people should increase their physical activity and reduce their caloric intake, and people with a family history of obesity should avoid calorically dense foods and select low-fat foods. (NAS Diet and Health Report, 1989) There are two kinds of fiber: insoluble fiber, which exerts its effects primarily in the digestive system, and soluble fiber, which has effects on substances in the blood stream. Diets high in both kinds of fiber tend to be bulky, and since fiber itself does not contribute calories, foods high in fiber tend to contain fewer calories in the same volume of food. These characteristics of high-fiber diets may help assuage hunger and thus contribute to weight loss. (NAS Eat for Life, 1992)


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Based on these authoritative statements, a structure function claim for fiber and satiety control may be justified. However, any food formulation targeting satiety control should be based on the review of individual ingredients recognizing that there are significant variations among fiber ingredients in the regulation of satiety. The following section provides a review of individual fiber ingredients.

Review of Fiber Ingredients Psyllium Psyllium mucilage is obtained from the coat of psyllium seeds (also called plantago or fleas seeds) by mechanical milling/grinding of the outer layer of these seeds. Psyllium has a gel-forming property in aqueous solutions. This gel-forming fraction of the alkali-extractable polysaccharides is composed of arabinose, xylose, and traces of other sugars (Singh and Chauhan, 2009). As shown in Table 14.1, all of the studies using more than 7 g of psyllium fiber showed positive effects on controlling satiety (Bergmann et al., 1992; Delargy et al., 1997; Nguyen et al., 1982; Rigaud et al., 1998; Stevens et al., 1987; Turnbull and Thomas, 1995). For example, psyllium (10.8 g) significantly delayed GE from the third hour after consumption of a meal and increased the sensation of satiety and decreased hunger at the sixth hour following the meal (Bergmann et al., 1992). However, two studies employing less than 5 g of psyllium showed no effects on measures of satiety (Table 14.2; Bianchi and Capurso, 2002; Frost et al., 2003).

Guar Gum Guar gum is a high molecular weight natural polymer that consists of a polymannan backbone with single galactose unit side chains, and is highly soluble and viscous in aqueous solutions (Chauhan et al., 2009). As shown in Tables 14.3 and 14.4, 11 out of the 16 studies on guar gum ingestion reported increased satiety (Adam and Westerterp-Plantenga, 2005a, 2005b; Chow et al., 2007; Ellis et al., 1981; French and Read, 1994; Heini et al., 1998; Hoad et al., 2004; Kovacs et al., 2002; Krotkiewski, 1984; Lavin and Read, 1995, Pasman et al., 1997). Five studies found no effect of guar gum on measures of satiety (Table 14.4; Kovacs et al., 2001; Mattes, 2007; Morgan et al., 1993; O’Donovan et al., 2005; van

236

Water (200 mL) and VAS, fat placebo (20 g intake granules with 200 mL water)

Standard meal—40 g VAS, GE CHO, 23 g lipid, 21 g protein

20 g Plantago ovate (20 g granules with 200 mL water)

10.8 g psyllium supplementation

15 g psyllium addition to base liquid GE

VAS, EI, GE

6.9 g placebo—15 minutes before the test meal (450 kcal: 21 g protein, 40 g CHO, and 23 g lipid) Base liquid: 24 g lactose in 480 mL water or 480 mL 2.5% low fat milk

7.4 g psyllium before the test meal

Measurement

Control

Test Diet

Table 14.1. Studies reporting positive effects of psyllium Results

Reference

Plantago ovate had a significantly higher fullness at 1 hour postmeal. Total fat intake was significantly lower in g/day and as a percentage of energy on the day of the meal after Plantago compared with water 12 healthy subjects; Psyllium significantly 6 hours delayed GE from the third hour after a meal. It

The addition of psyllium or cellulose modestly delayed GE at approximately 30 minutes

Bergmann et al., 1992

Turnbull and Thomas, 1995

Nguyen et al., 1982

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17 healthy females; 3 hours premeal and 3 hours postmeal

2 healthy subjects and 1 lactose malabsorber; 50 minutes

14 healthy subjects. Psyllium reduced hunger Rigaud et al., VAS—4 hours; feelings and EI; no effect on 1998 GE—200 minutes GE

Design


EI

VAS

Breakfast cereal with Comparison of 20 g fiber from psyllium versus WB wheat bran or psyllium

Delargy et al., 1995

Stevens et al., 1987


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23 g fiber/day; 4 g fiber/day crackers containing psyllium gum, WB, or a combination of the two fiber sources

22 g psyllium Low-fiber cereal with VAS, EI (soluble 17.5 g 3 g fiber insoluble 4.2 g) or wheat bran (WB: insoluble fiber) were incorporated into breakfast cereals

increased the sensation of satiety and decreased hunger at the sixth hour after the meal 16 healthy males; The psyllium breakfast ad libitum intake: produced a greater 1.5–7 hours after suppression of snack intake breakfast; dietary than the control breakfast, record–24 hours but smaller suppression than the WB breakfasts. Psyllium reduced hunger and voluntary EI (NS) compared with the WB much later in the day (9.5–13.5 hours after breakfast) 12 females; 2 Psyllium gum and weeks intervention combination supplements significantly decreased intake of digestible energy by 153 and 115 kcal/day, respectively First study—12; Psyllium produced greatest volunteers; second satiety 13.5 hours after study—16 breakfast volunteers; 24 hours


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White bread and one 70 g egg yolk

2 soluble (guar gum and ispaghula) and 1 insoluble fibers (microcrystalline cellulose); 5 g each Pasta with 1.7 g psyllium enrichment served with a tomato sauce GE

Measurement

Results

10 healthy subjects; No change in GE or the 4 hours incremental area under the curve for GLP-1

10 healthy subjects; Dietary fibers did not 24 hours significantly change GE.

Design

Frost et al., 2003

Bianchi and Capurso, 2002

Reference

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Pasta containing 50 g GE and of available postprandial carbohydrate GLP-1

Control

Test Diet

Table 14.2. Studies reporting no significant effects of psyllium


99 overweight and GG resulted in a 27.1% Chow et al., 2007 obese subjects with increase in fullness, a 15.8% NIDDM; 4 hours decrease in prospective consumption, and a 14.2% decrease in hunger in the

Commercial nutrition VAS control bars (CH; 6.4 g fiber)

300 kcal lunch consisting of GG-containing nutrition bars (9.1 g fiber)

(Continued)

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Adam and WesterterpPlantenga, 2005b

Adam and WesterterpPlantenga, 2005a

36 normal-weight subjects; 2 hours

Satiety was increased in normal-weight subjects compared with OW subjects in the GG condition at 30 (p = 0.02) and 60 (p = 0.04) minutes. GLP-1 concentrations were significantly increased after GG at 30 and 60 minutes compared with W in both groups Postprandial plasma GLP-1 concentrations after GG were significantly increased. Deltasatiety was significantly related to DeltaGLP-1 (W)

A galactose (50 g)/ Water (250 mL) and VAS, GLP-1 GG (2.5 g) load (836 the standard breakfast kJ) and a standard (W) breakfast

Reference

28 overweight/obese (OW) and 30 normal-weight subjects; 2 hours

Results

Water (250 mL) and VAS, GLP-1 the standard breakfast (W)

Design

A galactose (50 g)/ GG (2.5 g) load and a standard breakfast

Measurement

Control

Test Diet

Table 14.3. Studies reporting positive effects of guar gum (GG)


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240

Control

A 325-mL sweetened, VAS, GE milk-based meal-replacer beverage

Two types of alginates, which gel weakly or strongly on exposure to acid, compared with GG; 1% each

VAS, CCK, leptin

25 obese females. 5 weeks intervention; measurement up to 2 hours postmeal 12 volunteers; up to 4 hours

8 males; 50 minutes

VAS, GE

A 3.3 MJ (800 kcal) formula

11 nondiabetic subjects; 2 hours

Design

VAS

Measurement

French and Read, 1994

Ellis et al., 1981

Reference

Compared with the control meal, strong-gelling alginate and guar meals increased fullness and decreased hunger

Hoad et al., 2004

No changes in fasting blood Heini et al., 1998 levels of CCK and leptin and VAS scores

3% GG delayed the GE of the low-fat soup; the small delays in the return of hunger and decline of fullness were significantly correlated with the GE

Significant increases in satiety attributed to 100–150 g guar/kg bread

120–240 minutes postlunch areas under the curve (AUC) compared to CH

Results

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20 g fiber from GG

Bread supplemented Bread alone with GG at three levels (50, 100, and 150 g/kg) 3% guar gum was High- and low-fat added to high- and soups with 0 g guar low-fat soups

Test Diet

Table 14.3. (Continued)


VAS, EI, GE

VAS, EI

2% GG in a 250-mL, A 250-mL, 30% 30% glucose drink glucose drink; 0 g GG

20–40 g GG supplementation

Pasman et al., 1997

Lavin and Read, 1995

Daily hunger ratings Krotkiewski, recorded for up to 10 weeks 1984 showed that GG reduced hunger significantly better than commercially available bran taken in the same way

Satiety before the third Kovacs et al., meal was higher with SSM 2002 with GG compared to SSM without GG. Meal pattern, general appetite, and total EI were similar for all treatments

GG reduced the ratings for hunger and desire to eat and an increase in ratings for fullness and satiety. No changes in EI from the test meal and GE Obese women who Mean EI decreased had lost weight; 1 significantly from 6.7±0.4 week MJ to 5.4±0.2 MJ daily after GG supplementation. No changes in satiety ratings

10 healthy males; up to 3.5 hours after the drinks

Obese subjects; up to 10 weeks

15 overweight males; 2 week

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0 g GG supplementation

VAS

SSM and a solid meal VAS, EI (947 kJ)

20 g GG a day (10 g Bran supplement supplement twice daily)

2.5 g GG addition to a semisolid meal (SSM)


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Test meals containing GIP, GE 100 g carbohydrate

No effect on GE

GG addition to a semisolid had no effect on appetite, hunger and desire to eat as well as EI No significant treatment effects in self-reported appetitive sensations over each 5-hour postloading period. 4 g guar added glucose infusion (intraduodenal) —attenuated GLP-1 and GIP responses in elderly

Results

6 healthy nonobese GG and SBF lowered subjects; postprandial GIP levels. 200 minutes No effect on GE

8 males; 180 minutes

A standard semisolid test meal containing 0g

GE

8 healthy older subjects; 120 minutes after infusion

25 healthy overweight adults; 5 hours

Intraduodenal glucose GLP-1, GIP infusion (3 kcal/min)

VAS

55 g breakfast bar with and without 3.9 g alginate/bar

28 overweight males; 2 weeks

Design

Morgan et al., 1993

van Nieuwenhoven et al., 2001

O Donovan et al., 2005

Mattes, 2007

Kovacs et al., 2001

Reference

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Intraduodenal glucose infusion (3 kcal/min) with guar gum (4 g) for 1 hour A standard semisolid test meal containing 2.5 g, 3.5 g, or 4.5 g of GG Test meals with 10 g GG, 10 g soybean–cotyledon fiber, 10 g SBF, or 5 g glucomannan

VAS, EI

A low-energy SSM and a solid meal

Addition of modified guar gum (GG) to a low-energy semisolid meal 55 g breakfast bar (3.9 g GG/bar or 7% w/w)

Measurement

Control

Test Diet

Table 14.4. Studies reporting no significant effects of guar gum



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243

Nieuwenhoven et al., 2001). Overall, guar gum tended to promote satiety, most likely due to its gel-forming properties. As an ingredient, guar gum is relatively easy to handle and is a fairly low-cost substance in the hydrocolloid category.

Alginate Alginate is a linear polysaccharide, whose monomers are mannuronic and guluronic acids, and has a gel-forming property, especially in the presence of calcium ion (Panouillé and Larreta-Garde, 2009). A review of three studies on alginate indicates that alginate consistently promotes satiety probably through its gel-forming capacity, which contributes to slower GE (Table 14.5; Hoad et al., 2004; Paxman et al., 2008; Pelkman et al., 2007). Minimum level necessary to decrease EI appears to be 1.5 g/dose. Paxman et al. (2008) randomly assigned 68 normal-weight adults (an average age of 24.6) to either an alginate beverage (1.5 g of alginate/day) or an 18.2 g dose of SlimFast (Unilever) for 7 days. The alginate beverage group had a significant 7% reduction in daily EI (equivalent to about 135 kcal/day). The test beverage was composed of 1.5 g sodium alginate (Protanal from FMC BioPolymer, with a guluronate content of 65–75%), 0.7 g calcium carbonate, 2.8 g glucono-delta-lactone, 0.5 g sodium bicarbonate, 0.05 g malic acid, 0.24 g vanilla flavor, and 7 g fructose. The composition is reportedly patented under patent number WO2007039294. Although this carboxylic polymer can contribute to increased viscosity in the gastrointestinal tract by either acid-induced gelation or via calcium induced cross-linking (with coingestion of calcium), high material cost, sour taste, and difficult handling properties may limit food uses of alginate as a source of dietary fiber.

Oat β-Glucan Oat β-glucan consists of a mixture of β-(1,3) and β-(1,4)-glycosidic bonds, and has been known to lower blood cholesterol and glucose levels due to its viscosity, which is affected by concentration and molarity (Wood, 2004). Despite the high viscosity of oat β-glucan, two studies on oat β-glucan have reported no effects on satiety (Table 14.6; Hlebowicz et al., 2008; Juntunen et al., 2002).

244

Beverage with 0 g GG or alginate

1.0 g or 2.8 g beverage alginate-pectin formulations were tested Two types of alginates, which gel weakly or strongly on exposure to acid, compared with GG; 1% each A strong-gelling sodium alginate formulation VAS, EI

Measurement

Placebo

EI

Results

Reference

68 healthy subjects; Alginate formulation 7 days reduced EI

Paxman et al., 2008

29 healthy subjects. In women in the lower 50th Pelkman et al., week percentile of rigid restraint, 2007 GG reduced EI by 12% during the day and by 22% for the evening snack 12 volunteers Compared with the control Hoad et al., 2004 meal, strong-gelling alginate and guar meals increased fullness and decreased hunger

Design

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A 325-mL sweetened, Intragastric milk-based gelling, GE meal-replacer beverage

Control

Test Diet

Table 14.5. Studies reporting positive effects of alginate


White-wheat bread (WWB)

Wholemeal rye bread containing oat β-glucan concentrate or dark durum wheat pasta (95.6 g fiber from wheat), or whole-kernel rye bread

Reference

20 healthy subjects; No effect on GE and Juntunen et al., 3 hours GLP-1 2002

Results

VAS, GE rate 12 healthy subjects; No effect on GE rate Hlebowicz et al., 90 minutes and satiety 2008

GE, GLP-1, GIP

Measurement Design

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Extruded muesli product based Extruded muesli on 4 g oat β-glucan product with 0 g oat β-glucan

Control

Test Diet

Table 14.6. Studies reporting no significant effects of oat β-glucan


245


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246



Barley Barley and wheat are commonly used grains in diets. All the studies employing >62 g barley/dose consistently produced a positive impact on satiety (Table 14.7; Granfeldt et al., 1995; Liljeberg et al., 1999; Kaplan and Greenwood, 2002; Nilsson et al., 2008). However, as shown in Table 14.8, less than 50 g of barley had little effect on satiety (Keogh et al., 2007; Kim et al., 2006). Thus, it appears that barley exhibits a dose–response relationship in terms of satiety. Barley consists of two major fiber components: β-glucan and amylose. The results from studies on barley, HACS, and oat β-glucan suggest that the high amylose present in barley may have contributed to enhanced satiety effects.

Wheat and Wheat Bran As shown in Table 14.9, wholemeal wheat is also known to be effective in enhancing satiety (Grimes and Gordon, 1978; Holt and Miller, 1994; Holt et al., 1995). A satiety index (SI) score (approximately 160) of wholemeal bread was higher than that of white pasta (approximately 120), muesli (approximately 100), white bread (100), or croissant (approximately 35) (Holt et al., 1995). Studies report that whole-grain oat cereal and whole-wheat cereal have comparable satiety effects as measured by EI and VAS (Berti et al., 2005; Saltzman et al., 2001). However, durum wheat and processed wheat fiber neither promote gut hormonal gastric inhibitory polyreptide (GIP) responses nor slow GE (Table 14.10; Juntunen et al., 2002; Weickert et al., 2005, 2006b). A limitation of comparing these studies is that different end point measurements were assessed, which may partly contribute to the inconsistencies in the findings between various researchers. Wheat bran was effective in promoting satiety when wheat bran cereals were compared with low-fiber cereals (Table 14.11; Delargy et al., 1995, 1997; Hlebowicz et al. 2008; Levine et al., 1989). Although, wheat bran showed no efficacy when it was incorporated into other forms of diet (Table 14.12; Beck et al., 1986; Morgan et al., 1993; Sandstrom et al., 1983; Stevens et al., 1987). The data indicate that food form is another important factor determining the satiety effects of fiber ingredients. Wheat showed comparable satiety effects when compared with chickpeas (Pittaway et al., 2007) or rye (Heinonen et al., 2007).

Soy Fiber, Oat Hull Fiber, and Sugar Beet Fiber Soy fiber, oat hull fiber, and sugar beet fiber (SBF) are not viscous in aqueous solutions (Howarth et al., 2001; Weickert et al., 2005). Oat hull

VAS

The highest satiety score was associated with the barley breakfast

Results

All barley products elicited higher satiety scores when compared with WWB 15 healthy subjects. The evening meal with Measured second HBB bread resulted in a meal effects higher satiety score (AUC no I. IAUC 180 minutes) after the standardized breakfast with after all other evening meals

10 health subjects; 4 hours after breakfast; 3 hours after second meal 10 healthy subjects; 2 hours

Design

(Continued)

Nilsson et al., 2008

Granfeldt et al., 1995

Liljeberg et al., 1999

Reference

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50 g available starch–-WWB

50 g available CHO; white bread

WWB (50 g starch) VAS

Bread with 60% barley flour; bread with barley flour + barley flakes (containing 17% β-glucan) 79.1 and 90.2 g normal and high-amylose barley flour (porridge; 50 g available CHO) WWB with ordinary barley (OB), high-amylose barley (HAB), enriched barley β-glucan (HBB) or 100 g HACS (RS), or WWB with the same amount of RS and also with DF from barley (RS+DF)

Measurement

Control

Test Diet

Table 14.7. Studies reporting positive effects of barley


247

248

Control Iso-CHO (Available CHO 46.6 g) nonenergy placebo drink

Test Diet

Barley, glucose drink, or potatoes


VAS, FI

Measurement 10 healthy subjects; 120 minutes postingestion period, followed by consumption of an ad libitum lunch

Design

Reference

Potatoes increased satiety Kaplan and the most, followed by Greenwood, barley, then glucose, 2002 which trended toward greater satiety than placebo. Potatoes led to less hunger than placebo and less prospective consumption than the other three foods Potatoes and barley led to greater fullness than glucose and placebo

Results

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Wheat containing meal; 5 g fiber, 25 g available CHO

30 g barley cereal, 8 g fiber, 19 g available CHO

VAS, FI

19 overweight subjects; 150 minutes

14 healthy women consumed a test breakfast. Crossover. 10 hours

Measurement Design

Reference

The ingestion of 1–2 g of β-glucan did not change VAS ratings, which rate their hunger, fullness, satisfaction, and thirst, at timed intervals

Kim et al., 2006

Meal type did not affect any Keogh et al., variable measured by the 2007 VAS. Ad libitum FI over the next 10 hours was reduced by 23% (9.6 vs. 11.0 MJ, p < 0.05) after the wheat-containing meals compared to the barley-containing glycaemic index meals

Results

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2 g, 1 g, or 0 g β-glucan Isocaloric test meals: VAS (50 g or 25 g barley) a glucose solution or from barley wheat, a wheat–barley mixture (1 g β-glucan), or barley (2 g β-glucan)

Control

Test Diet

Table 14.8. Studies reporting no significant effects of barley


249

250

Compared the amount eaten to reach fullness

Grimes and Gordon, 1978

Wholemeal bread required less quantity than white bread to reach fullness

VAS

10 healthy subjects; 120 minutes

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VAS

WWB

Reference

Wholemeal wheat bread

Results

Meals with fine wholemeal flour

Design

Meals with whole grains, cracked grains, or coarse wholemeal flour

Measurement

101 g of wholemeal bread Holt et al., 1995 resulted in a higher SI score (approximately 160) than white pasta (approximately 120), muesli (approximately100), white bread (100), or croissant (approximately 47) The fine flour meal had the Holt and Miller, lowest satiety response 1994 (AUC: 231.4 +/−31.6) and the whole grain meal had the highest response

Control

101 g wholemeal Isoenergetic 1,000 kJ A satiety index 11–13 subjects; 120 bread (240 kcal) servings of (SI) score minutes 38 foods separated into six food categories

Test Diet

Table 14.9. Studies reporting positive effects of wholemeal wheat


GLP-1, GIP

VAS, GLP-1, GIP

Bread with 10.5 g wheat White bread fiber

Bread with 10.5 g wheat White bread fiber or 10.5 g oat fiber

Measurement GE, GLP-1, GIP

Control

Dark durum wheat pasta WWB (95.6 g fiber from wheat), whole-kernel rye bread, or wholemeal rye bread containing oat β-glucan concentrate

Test Diet

Results

20 healthy subjects; No effect on GE, GIP, and 3 hours GLP-1 responses, except for GLP-1 responses to the rye bread containing oat β-glucan concentrate, which were lower after the consumption of rye breads and pasta than after consumption of WWB 14 healthy women; GIP at 180 minutes— 5 hours significantly lower after wheat fiber, GLP-1—no effect 14 healthy women; No effect on GLP-1; no 5 hours effect in hunger scores. Postprandial responses of PYY and ghrelin were blunted after the intake of wheat fiber

Design

Table 14.10. Studies reporting no significant effects of wholemeal wheat or wheat fiber

Weickert et al., 2006b

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Weickert et al., 2005

Juntunen et al., 2002

Reference


251

252

Bran flakes with sour milk

Corn flakes or oat flakes with sour milk

First experiment— 12 healthy; second experiment—16 subjects; 24 hours GE rate, VAS 12 healthy subjects, 90 minutes

VAS


Bran flakes slowed the GE Hlebowicz et al., rate when compared to oat 2008 flakes and corn flakes. No effect on satiety

WB produced greatest satiety shortly after consumption

8:28

Breakfast cereal with Comparison of 20 g fiber from wheat psyllium versus WB bran or psyllium

Levine et al., 1989

Reference

WB cereal reduced Delargy et al., short-term hunger ratings 1997 (1.5 hours), no significant effect of breakfast type on total day EI.

16 healthy subjects; ad libitum EI was assessed at 1.5 hours (snack) after breakfast, later in the day (food box), and the following day

Low-fiber cereal and cereal with psyllium

VAS, EI

14 healthy subjects; Fiber cereals reduced FI 6 hours without the perception of feeling less hungry

Results

Low-fiber cereal plus VAS, FI milk and orange juice

Design

57 g All Bran, Fiber One, Shredded Wheat, and other breakfast cereals Cereal breakfast with wheat bran (22 g fiber; 18.1 g insoluble and 3.8 g soluble)

Measurement

Control

Test Diet

Table 14.11. Studies reporting positive effects of wheat bran


4 g/day fiber control

Crackers containing psyllium gum, wheat bran, or a combination of the two fiber sources (23 g fiber/day)

Results

12 females; 2 weeks

No effect on EI

Basal levels of the three hormones were not affected by bran ingestion. WB decreased GIP response to the test meal only 10 constipated The FI was generally patients in geriatric satisfactory and decreased ward, 6–12 weeks in only two women on bran treatment 6 volunteers; Wheat bran—no effect on 200 minutes GIP or GE

5 healthy men; 7 weeks

Design

Stevens et al., 1987

Morgan et al., 1993

Sandström et al., 1983

Beck et al., 1986

Reference

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EI

GIP, GE

100 g CHO meal

Comparing 10 g wheat bran, 10 g SBF, 10 g guar gum, and 10 g soy fiber and 5 g glucomannan

GIP, gastrin, vasoactive intestinal polypeptide (VIP) FI, 5-day food records after 6 and 12 weeks

0 g WB

Wheat bran addition to normal diet; 20 g/day

Measurement

Ordinary or low-phytate 0 g WB wheat bran addition to their diet; 20 g/day

Control

Test Diet

Table 14.12. Studies reporting no significant effects of wheat bran


253


254

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fiber has become an important food ingredient due to its high fiber content (about 90%). The results of two studies using oat hull fiber suggest that this food ingredient has little effect on satiety; oat hull fiber accelerated GIP responses without affecting hunger scores or GLP-1 and PYY responses (Table 14.13; Hlebowicz et al., 2008; Weickert et al., 2005, 2006a, 2006b; Zarling et al., 1994). Similarly, studies on soy fiber showed no effect on GE (Table 14.14; Bouin et al., 2001; Morgan et al., 1993; Zarling et al., 1994). Gastric emptying and gastric acid secretion in healthy adults were unaffected when a supplementation of an enteral diet with 7.5 g soy polysaccharides (500 kcal, 250 mL/h) was consumed (Bouin et al., 2001). Morgan et al. (1993) also reported that 10 g of soy fiber in a test meal containing 100 g carbohydrates had no effect on GIP response and GE. A study employing a mixture of soy fiber and oat hull fiber (28.8 g/day, 10 days) showed no effect on GE in medically stable residents of a chronic care facility (Zarling et al., 1994). The end points employed in the studies on soy fiber are GE and/or gut hormones, not actual satiety. It may be premature to conclude that soy fiber does not have satiety effects; thus, more studies are needed. It appears that sugar beat fiber does not have a significant inpact on satiety (Table 14.15).

Inulin, Oligofructose (OF), and Polydextrose Cani et al. (2006) reported that supplementation of 16 g OF/day for 2 weeks increased short-term satiety measures. In this study, subjects completed two 2-week experimental phases during which they received either 16 g of OF (8 g with breakfast and 8 g with dinner) or a placebo (maltose) (Table 14.16). During breakfast, OF significantly increased satiety compared to placebo treatment, but without affecting other measures of satiety. After lunch, no significant differences were observed between treatment periods. At dinner, OF significantly increased satiety and reduced hunger (p = 0.04) and prospective food consumption. The EI at breakfast and lunch were significantly lower after OF treatment than after placebo treatment. Total daily EI was 5% lower during OF than the placebo period. Archer et al. (2004) reported that supplementation of 24 g inulin/day induced a lower EI during the test day, even though it had no effect on satiety at the breakfast. The authors suggested that a late postabsorptive satiety effect may be related to the fermentation of inulin. However, two studies on inulin showed no effect on GE (Table 14.17; Den Hond et al., 2000; Geboes et al., 2003). Differences between inulin and OF may be partly explained by the fact that long-chain inulin is largely fermented in the

White bread

White bread

Bread enriched with 10.5 g oat fiber

Bread enriched with 10.5 g oat fiber, 10.8 g wheat fiber, or 10.4 g RS subgroups Fiber-enriched bread (white bread enriched with 31.2 g oat fiber/day)

Oat flakes with sour milk

Corn flakes with sour milk

14 healthy women; 5 hours

5 hours

Design No effect on hunger scores and postprandial responses of PYY and ghrelin

Results

Oat fiber was associated with earlier GIP responses; no effect on GLP-1 Plasma ghrelin, 17 overweight or No effect on plasma and obese subjects with ghrelin, and adiponectin adiponectin, normal glucose concentrations, as well body weight metabolism; as substrate utilization 72 hours and body weight GE 10 medically stable No effect on GE. Oat resident patients; 10 fiber increased fecal days intervention; energy 140 minutes postmeal GE rate, VAS 12 healthy subjects, No effect on satiety or 90 minutes satiety

GIP, GLP-1

VAS, PYY, gherlin

Measurement

Hlebowicz et al., 2008

Zarling et al., 1994

Weickert et al., 2006b

Weickert et al., 2005

Weickert et al., 2006a

Reference

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Enteral nutritional Enteral nutritional formula with a mixture formula of a 50% soy and 50% oat fiber (28.8 g/day)

White bread

Control

Test Diet

Table 14.13. Studies reporting no significant effects of oat fiber


255

256

Enteral nutritional Enteral nutritional formula with a mixture formula of a 50% soy and 50% oat fiber (28.8 g/day)

10 medically stable resident patients; 10-day intervention; 140 minutes postmeal

6 healthy nonobese subjects; 200 minutes

12 healthy volunteers; 3 hours

Design

Bouin et al., 2001

Reference

No effect on GE. A mixture of soy fiber and oat fiber increased fecal energy

Zarling et al., 1994

Soy fiber, SBF, and Morgan et al., wheat bran had no effect 1993 on GIP concentrations and GE

No significant effect on GE and gastric acid secretion

Results

8:28

GE

GIP, GE

Test meals containing 100 g carbohydrate

Test meals with 10 g soybean–cotyledon fiber (Fibrim), 10 g guar gum, 10 g SBF, or 5 g glucomannan

Measurement GE

Control

Enteral diet with soy Enteral diet with polysaccharide fiber or 0 g fiber mixed fiber from pea and inulin

Test Diet

Table 14.14. Studies reporting no significant effects of soy fiber


PYY GIP, GE

GIP, GE

Hormonal responses

0g Test meals containing 100 g carbohydrate

Test meals containing 100 g carbohydrate

No fiber

40 g Fibrex, 27 g DF daily Test meals with 10 g SBF, 10 g soybean–cotyledon fiber, 10 g guar gum, or 5 g glucomannan Test meals with 10 g SBF, 10 g soybean–cotyledon fiber, 10 g guar gum, or 5 g glucomannan

Measurement

Control

Test Diet

Table 14.15. Studies reporting no significant effects of SBF

3 hours

SBF increased GIP response



No changes in PYY

Results

Hagander et al., 1986

Morgan et al., 1990

Hagander et al., 1989 Morgan et al., 1993

Reference

8:28

6 healthy nonobese subjects

12 NIDDM subjects; 8 weeks 6 healthy nonobese subjects

Design


257

258

Maltodextrin

Standard enteral formula

OF-Raftilose P95 (8 g twice daily—once at breakfast and once at dinner)

Enteral formula with pea-fiber (10 g/L) and FOS (5 g/L) EI, VAS

VAS

VAS

Measurement

Results

11 healthy subjects; Consumption of the 14 days pea-fiber/FOS formula resulted in higher mean fullness 33 men; VAS— Inulin reduced EI 285 minutes; EI— without changing the 24 hours satiety responses

10 persons; 2 weeks OF treatment increased satiety following breakfast and dinner, reduces hunger and prospective food consumption following dinner

Design

Archer et al., 2004

Whelan et al., 2006

Cani et al., 2006

Reference

8:28

Half the fat of a full-fat A full-fat sausage sausage patty is patty replaced with inulin or with lupin-kernel fiber

Control

Test Diet

Table 14.16. Studies reporting positive effects of and inulin



8:28


Fiber and Satiety

259

Table 14.17. Studies reporting no significant effects of and inulin Test Diet

Control

Measurement Design

Results

15 g inulin/day

Sucrose

GE

No effect on Den Hond GE et al., 2000

Test meal Test meal with 5 or with 0 g 10 g inulin inulin (Raftilin HP)

GE

6 healthy subjects; 2 weeks Healthy subjects; 180 minutes plus

Reference

No effect on Geboes GE et al., 2003

distal colon, whereas OF is fermented in the proximal colon. Thus, inulin may not be able to produce the same effect as OF in terms of GLP-1 (Cani et al., 2006). Polydextrose showed inconsistant effects (Table 14.18; King et al., 2005; Willis et al., 2009).

Resistant Starches (RS) Starches and degradation products of starch that resist enzymatic digestion in the small intestine are classified as RS (Finocchiaro et al., 2009). Such indigestible materials pass to the large intestine where they can be fermented and act as a fiber in the body. RS are typically classified into four fractions: RS1 through RS4 . Where RS1 is physically inaccessible or digestible and can be found in seeds or legumes and unprocessed whole grains; RS2 occurs in a natural granular form, for instance uncooked potato and high-amylose corn; RS3 is formed when starch-containing foods are cooked and cooled such as in bread or retrograded high-amylose corn; and RS4 are starches that have been manufactured or chemically modified to resist digestion (Sajilata et al., 2006). High-amylose corn starch (HACS) and ingredients prepared from this starch are examples of natural RS (RS2 and RS3) and have been the focus of substantial research including many of the following selected studies. As shown in Table 14.19, studies based on isocaloric comparisons of RS and placebo tend to show positive effects of RS on satiety (Qu´ılez et al., 2007; van Amelsvoort and Weststrate, 1992; Willis et al., 2009). Satiety effects were weakened when placebo was replaced with an equal weight of HACS resulting in a lower caloric content of the RS group (Table 14.20; Anderson et al., 2002; Weststrate and van Amelsvoort, 1993).

260

Preload-yogurt

Control VAS, EI

Measurement

Results

Reference

20 healthy subjects; Polydextrose muffin had Willis et al., 2009 3 hours the least impact on satiety (less than the control muffin)

15 healthy subjects; When the energy content King et al., 2005 1.5 hours of the yogurt preloads were accounted for, there was a significant suppression of energy intake for P (yogurt + 25 g polydextrose) compared with C (p = 0.002). The XP yogurt (yogurt + 12.5 g xylitol and 12.5 g polydextrose) induced a significantly stronger satiating effect

Design

8:28

No significant effects High-fiber muffin Isocaloric low-fiber VAS enriched with muffin (1.6 g polydextrose, corn fiber;178 kcal) bran, RS or barley β-glucan with oat fiber (8.0–9.6 g fiber; 174–177 kcal)

Positive effects Preload-yogurt containing 12.5 g xylitol, 12.5 g polydextrose (P), 12.5 g xylitol plus 12.5 g polydextrose (XP)

Test Diet

Table 14.18. Studies reporting effects of polydextrose


VAS

VAS

VAS

Isocaloric low-fiber muffin (1.6 g fiber;178 kcal)

100 g pastas, 19% E from protein, 23% fat, 53% polysaccharides

Bread—50 g available CHO

High-fiber muffin enriched with Hi maize RS(RS2 RS3), polydextrose, corn bran, or barley β-glucan with oat fiber (8.0–9.6 g fiber; 174–177 kcal) 20% of wheat flour was replaced by 70% or >75% high amylose—(24.5% of CHO); or regular corn starch 40% of flour was replaced by HACS in low-calorie muffins (6.3 g fiber; 102 g serving size vs. 1.5–2.7 g fiber control)

Measurement

Control/Diet

Amount Fed

Table 14.19. Studies reporting positive effects of RS

The satiety response of low-calorie (HACS) muffins (SI = 100) was similar to bread (SI = 100) and higher than plain muffins (SI = 52: p = 0.02).

Fullness/satiety score was higher after high-amylose meals

Subjects were more satisfied after eating RS or corn bran than after polydextrose.

Results

(Continued)

Qu´ılez et al., 2007

Hospers et al., 1994

Willis et al., 2009

Reference

8:28

14 healthy or overweight subjects; 2 hours

16 healthy males; 3 hours

20 volunteers; 3 hours

Design


261

262

Control/Diet

60 g fiber from RS ingredient (100 g Novelose 260)

VAS

Measurement

Low RS GLP-1 diet-supplemented with 40 g waxy-maize starch

Hot mixed lunch in which Low-amylose diet Amylose:Amylopectin (Am:Ap = 0:100) (Am:Ap) was 45:55

Amount Fed


10 healthy subjects. Low-fiber diet for 24 hours, then meal tolerance test (MTT) the following morning

24 healthy males; 6 hours

Design

van Amelsvoort and Weststrate, 1992

Reference

Plasma GLP-1 during Robertson et al., the MTT rose from a 2003 mean basal level of 11 pmol/L to reach a mean peak concentration of 42 pmol/L after 1 hour. There was no effect of preceding diet on the plasma GLP-1 excursion

High-amylose meals induced more satiety up to 6 hours postprandially.

Results

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50 g available starch—WWB

WWB with ordinary barley (OB), high-amylose barley (HAB), enriched barley β-glucan (HBB) or 100 g HACS (RS), or WWB with the same amount of RS and also with DF from barley (RS+DF) VAS, FI

VAS

Measurement

14 healthy subjects

15 healthy subjects; measured second meal effects

Design

Carbohydrates with a high GI (glucose, polycose, and sucrose) suppressed subjective appetite and FI in the short term, but those with a low GI (amylose and amylopectin) did not.

RS may have slightly better satiety scores than WWB. The evening meal with HBB bread resulted in a higher satiety score (IAUC 180 minutes) after the standardized breakfast with after all other evening meals

Results

(Continued)

Anderson et al., 2002

Nilsson et al., 2008

Reference

8:28

Compared with Beverages amylopectin, polycose, a containing 75 g fructose–glucose CHO mixture, sucralose, and glucose

Control/Diet

Test Diet

Table 14.20. Studies reporting no significant effects of RS


263

264

Pasta containing RS

Normal pasta

EE, VAS, Ghrelin, GLP-1, PYY

30 subjects; 3 hours after lunch

24 healthy males; up to 4 weeks

0g supplementation

RS supplementation had no acute effect on substrate utilization, appetite feelings, and gut-derived hormones.

Consumption of 30 g/ day RS2 and RS3 had little influence on appetite and FI

No systematic effect of amylose content on appetite or fullness ratings

Results

Smeets et al., 2008

de Roos, 1995

Weststrate and van Amelsvoort, 1993

Reference

8:28

VAS, FI

22 healthy males; 4 hours after breakfast and 6 hours after lunch

Breakfast with a VAS low-amylose starch. Pizza lunch with 25.5 g common maize starch

Design

40 g CHO (14 g amylose) at breakfast and 46 g CHO (16 g amylose or 25 g high-amylose maize starch) at lunch (pizza) 30 g RS/day

Measurement

Control/Diet

Test Diet




Fiber and Satiety

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265

The study conducted by Willis et al. (2009) compared several fibers, including commercial RS ingredients derived from HACS. Their results suggested that all fibers do not influence satiety equally and that natr r 260 and Novelose 330) was the ural RS (a mixture of HiMaize most effective in enhancing short-term satiety among the various fibers tested. In this study, 20 healthy subjects, aged 18–65 years, consumed either a low-fiber control muffin (1.6 g) or one of four high-fiber muffins (8.0–9.6 g fiber), which contained nearly identical macronutrient content (175 kcal). The test supplements were corn bran, barley β-glucan with oat fiber, polydextrose, or HACS. On the morning of each test, subjects completed a previously validated 100 mm VAS to assess hunger and appetite (baseline). Additional VAS were completed at 15, 30, 45, 60, 120, and 180 minutes after consumption of muffins. At 45 minutes, subjects were more significantly satisfied after eating a muffin with HACS (p = 0.0009) or corn bran (p = 0.0118) than a muffin with polydextrose or the control muffin. Subjects were significantly less hungry at 180 minutes after consuming either HACS (p = 0.0009) or barley with oat fibers (p = 0.024) than after consuming polydextrose. Similarly, subjects felt more satisfied after either HACS (p = 0.004) or corn bran (p = 0.028) than polydextrose. As previously mentioned, and as indicated in Table 14.19, RS has been shown to have positive effects on satiety (Qu´ılez et al., 2007; van Amelsvoort and Weststrate, 1992). Mechanisms by which RS may promote satiety include the effect of fermentation and resulting butyrate production, reduced glycemic and insulinemic responses, and possibly gut viscosity (Hamer et al., 2008). Several studies have suggested RS fermentation was the key trigger indicating satiety (Bird et al., 2007). Breath hydrogen, an indicator of colonic fermentation, also correlated positively with satiety (r = 0.27; p < 0.01) and inversely with GE rate (r = −0.23; p < 0.05) (Nilsson et al., 2008). Other studies demonstrated that RS also plays a role in reduction of postprandial blood glucose and insulin responses, which may be linked to increased satiety (Anderson et al., 2002; Behall et al., 2006; Bornet et al., 2007; Noakes et al., 1996; Qu´ılez et al., 2007; Robertson et al., 2003, 2005; van Amelsvoort and Weststrate, 1992).

Conclusions All dietary fibers are not the same. It appears that viscous fibers such as psyllium, guar gum, and alginate are effective in promoting satiety.


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However, the effect of increasing the feeling of satiety still needs to be proven for insoluble, nonviscous fibers such as oat fiber, soy fiber, and SBF. The feelings of satiety produced by certain fiber ingredients have been acknowledged by authoritative bodies, including the potential health benefits resulting from the effect of fiber on satiety, such as the implication it has for weight control. Therefore, based on the scientific evidence, a structure function claim for general fiber in relation to its ability to control satiety may be justified. However, claims for individual fiber ingredients should be established based on findings specific to the particular ingredients since all dietars fibers are not the same.

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APPENDIX

Global Suppliers of Ingredients for Weight Control Fiber and Carbohydrate-Based Ingredients National Starch for Hi Maize 5 in 1 fiber and Novelose www.foodinoovation.com Headquarters National Starch and Chemical Company 10, Finderne Ave Bridgewater, NJ 08807, USA Phone: 1-800 743-6343 UK, Ireland, Nordic Europe Dagmar Krappe Gruener Deich 110 20097 Hamburg, Germany Phone: +49 (0) 40-23915-0 Australia 7–9 Stanton Road Seven Hills, Sydney NSW 2147, Australia Phone: +61 2-9624-6022 277


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Roquette for NUTRIOSE: resistant dextrins www.roquette.com Headquarters ROQUETTE FRERES La Haute Loge 62080 Lestrem cedex, France Phone: + 33 3 21 63 36 00 Fax: + 33 3 21 63 38 50 Roquette America, Inc. 1417 Exchange Street Keokuk, IA 52632 Phone: 319-524-5757 Fax: 319-526-2345 FMC for hydrocolloids including alginate www.fmc.com Headquarters 1735 Market Street Philadelphia, PA 19103, USA Phone: 1-215-299-6000 Fax: 1-215-299-5998 TIC gums for hydrocolloids including alginate www.ticgums.com Headquarters 4609 Richlynn Dr. Belcamp, MD 21017, USA Phone: 1-410-273-7300

Lipid-Based Ingredients Cognis Nutrition and Health for conjugated linolenic acid http://www.cognis.com

Appendix


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Appendix

Head Office: Cognis GmbH Postfach 13 01 64 40551 Düsseldorf, Germany Phone: +49 211 7940 0 Cognis North America Headquarters 5051 Estecreek Drive Cincinnati, OH 45232-1446, USA North America Phone: 1-800-254-1029 International Phone: +1-513-482-3000 Cognis Australia Pty. Ltd. 4 Saligna Drive Tullamarine VIC, 3043, Australia Phone: +61 3 9933 3500 Fax: +61 3 9933 3582 Cognis Japan Ltd. 20F Sphere Tower Tennoz 2-2-8 Higashi-Shinagawa Shinagawa-ku Tokyo 140-0002, Japan Phone: +81 (0)3 5769 6440 Fax: +81 (0)3 5769 6439 DSM Nutritional Products, Inc. for novel fat emulsion (Fabuless) www.dsm.com Headquarters: 45 Waterview Blvd Parsippany, New Jersey 07054, USA Phone: 1-908- 475-7412 Lipid Nutrition B.V. for PinnothinTM (Korean pine nut oil) www.lipidnutrition.com Head Office: Hogeweg 1 1520 AA Wormerveer, The Netherlands

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Appendix

Direct Phone: +31 (0)75 629 22 11; +31 (0)75 629 2911 Fax: +31 (0)75 629 28 17 [email protected] Lipid Nutrition B.V. North America W. Durkee Road 24708 Channahon, IL 60410, USA Phone: +815 730 5244 [email protected] Lipid Nutrition B.V. Asia Pacific Level 10, Two IOI Square Putrajaya, Malaysia 62502 Phone: +603 8947 8888 The Procter & Gamble Company for sucrose polyester (Olestra) www.pgfoodingredients.com www.olean.com Customer Service P&G Food Ingredients 11530 Reed Hartman Hwy Cincinnati, OH 45241, USA Phone: 1-800-477-8899

Protein-Based Ingredients GELITA Group AG for Gelatine (GELITA) www.gelita.com Headquarters: Gammelsbacherstr. 2 69412 Eberbach, Germany Phone: +49 (0) 62 71 / 84 - 01 Fax: +49 (0) 62 71 / 84 - 27 00 GELITA USA Inc. 2445 Port Neal Industrial Rd. Sergeant Bluff, IA 51054, USA Phone: +1 712 943 5516 Fax: +1 712 943 3372


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Appendix

281

GELITA Mexico S. de R.L. de C.V. Emiliano Zapata S/N Col. Emiliano Zapata Lerma, Mex. C.P. 52000, Mexico Phone: +52 7 28 / 285 0101 Fax: +52 7 28 / 285 1856 GELITA Nederland B.V. Handelsweg 24 9563 TR Ter Apelkanaal, The Netherlands Phone: +31 (0) 5 99 / 34 57 00 Fax: +31 (0) 5 99 / 47 05 08 GELITA Australia Pty. Ltd. (P.O. Box 276, Botany NSW 1455) Unit L2, Level 2, 2 A Lord Street Botany NSW 2019, Australia Phone: +61 (2) 95 78 - 70 00 Fax: +61 (2) 95 78 - 70 50 National Dairy Council for dairy products including whey protein and casein www.nationaldairycouncil.com 10255 West Higgins Rd, Suite 900 Rosemont, IL, USA [email protected] Phone: 1-312-240-2880; 1-847-803-2000 Agri-Mark for whey protein www.agrimarkwheyprotiens.com Phone: 1-608-783-9755 Fax: 1-608-783-9778 American Casein Company for casein www.americancasein.com Phone: 1-609-387-3130 Fax: 1-609-387-7204


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Davisco Foods for whey protein www.daviscofoods.com Phone: 1-800-757-7611 or 952-914-0400 Fax: 952-914-0887 Meiji for dairy products www.meiji-milk.com Tokyo, Japan Phone: +81-3-5653-0305 Fax: +81-3-5653-0290 Solae for soy protein www.solae.com 4300 Duncan Avenue St. Louis, MO 63110, USA Phone: 1-800-325-7108

Other Ingredients Pharma Foods International for green tea extracts www.pharmafoods.co.jp Phone: +81-75-394-8600 Fax: +81-75-394-0099 Lonza for l-carnitine and derivatives www.carnitine.com Phone: 800-955-7426 Fax: 201-794-2695 [email protected] Orcas International for l-carnitine www.orcas-intl.com Phone: 973-252-7100 Fax: 973-252-7104 [email protected] InterHealth for hydroxycitric acid www.interhealthusa.com Phone: 707-751-2800 Fax: 707-751-2802

Appendix

P1: OTA/XYZ P2: ABC ind BLBS044-Cho October 13, 2009

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Index ACO. See Acyl-CoA oxidase (ACO) Activated protein kinase (AMPK), 143 regulation of ROS and, 183–184 Acyl-CoA oxidase (ACO), 169 Adipocyte marker proteins, antiadipogenic effect of green tea and, 186–187 Adipocytes, and obesity, 177–178 Adipocyte-specific secretory factor (ADSF), 182 Adipogenesis, soy peptides reduces adiposity by inhibition of, 144–147 Adipose tissue, role in obesity, 97–98 Adiposity reduction, by soy peptides inhibiting lipid absorption and regulation of lipid metabolism, 141–143 inhibition of adipogenesis, 144–147 Ad libitum, 12 ADSF. See Adipocyte-specific secretory factor (ADSF) Air displacement pletismography (Bod Pod), 9 α-lactalbumin, 113–115 Alginate, 243 studies reporting positive effects of, 244 Amino acids arginine (ARG), 129 AMPK. See Activated protein kinase (AMPK) Animal models, to study effects of calcium and dairy intake, 80–81 Anthropometry–skinfold measurements, for measuring body fat, 9

Antiadipogenic effect of EGCG CDK 2 dependent signaling pathway, 182–183 via activation of AMPK, 183 via ERK dependent signaling pathway, 180–182 via regulation of ROS, 183–184 via resistin, 182 of green tea via downregulation of adipocyte marker proteins and its target genes, 186–187 via inhibition of lipogenic enzymes, 184–186 Appetite, 26 CCK release and effects on, 27 Satiety hormones effects on, 27 serotonin in regulation of, 110 ARG. See Amino acids arginine (ARG) Barley, 246 studies reporting no significant effects of, 249 studies reporting positive effects of, 247–248 β-conglycinin hydrolysates, 145, 147 BIA. See Bioelectrical impedance (BIA) Bioactive peptides, 136 Bioelectrical impedance (BIA), 9 Black soy peptide (BSP), 140–141 BMI. See Body mass index (BMI)

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284 Body composition. See also Body weight calcium and dairy products effects on, 70–73 changes after consumption of control/high-catechin, 190–191 CLA effects on, 8–9 clinical studies of CLA on, 10–15 exercise subjects with BMI less then 25, 12 long-term studies, 10–11 in subjects with BMI greater then 25, 12–13 methods for measuring, 9–10 satiety of high-protein diet and change in, 128–129 Body fat control, in animals by RD, 222 Body fat mass, CLA mechanism for decreasing, 5–6 Body fat reduction. See also Adiposity reduction by CLA, 6–15 effect on body shape, 13 effects on body composition and body weight, 8–10 meta-analysis study, 14–15 overview, 6–7 quality of material used for, 7–8 effects of high-calcium and high-dairy diets on, 71 Body mass index (BMI) body weight and, 9 CLA and exercise subjects with less then 25, 12 CLA and subjects with greater then 25, 12–13 Body shape, and CLA, 13 Body weight. See also Body composition calcium and dairy products effects on, 70–73 CLA effects on, 8–9 green tea effects on, 164–166 methods for measuring, 9–10 reduction by soy peptides, 143–144 role of calcium consumption on, 79 β-pancreatic cells, 97 BSP. See Black soy peptide (BSP)


Index Caffeine. See also Capsaicin efficacy of long-term experiments for, 166–167 short-term experiments for, 163–164 food/supplement applications of, 170–171 global suppliers of, 171 mechanisms of action of, 167–169 patent of, 171 safety of, 169–170 Calcium. See Dietary calcium Calcium modulation, of adiposity, 81 Calipers, for measuring body fat, 9 Caloric intake. See also Food intake in adults during 1971-2000, 44 efficacy of Olibrar and, 56–58 PinnoThinTM FFA effects on, 35 Caloric value, of RD, 219–220 cAMP. See Cyclic amino mono phosphate (cAMP) Capsaicin, 201–208. See also Caffeine effects on feeding behaviors, 203–205 efficacy of, 202–206 food/supplement applications of, 207 weight control and, 208 mechanism of actions, 206 overview, 201–202 patents on, 207 role in weight control, 207–208 safety of, 206–207 suppliers of, 208 thermogenic effect of, 203 Capsicum, 202 CARDIA. See Cumulative incidence observational population-based prospective study (CARDIA) Carnitine palmitoyltransferase (CPT) activity, 6 Casein, 123 effects on satiety long-term, 126–127 short-term, 123–126 food supplement applications of, 130 global suppliers of, 130 patents on, 130


22:45


Index Catechins and caffeine, 168–169 effect on gene expression of UCP, 169 green tea, 167 Catechol-O-methyltransferase (COMT), 167 CCK. See Cholecystokinin (CCK) CCK1 R. See CCK1 receptor (CCK1R) CCK1 receptor (CCK1 R), 140 CCK receptors, 140 CDK 2. See Cyclin-dependent kinase 2 (CDK 2) Central nervous system, regulation of satiety and FI by, 229–233 Cheese, 83 r , 105 Cheese product versus GELITA Chocolate dessert, ingredients of, 106 Cholecystokinin (CCK), 26 effects on appetite, 27 PinnoThinTM effects on releasing, 29–30, 31–32 regulation of FI, 232 released in proximal small intestine, 26 c-Jun-N-terminal kinases (JNK), 180 CLA. See Conjugated linoleic acids (CLA) Claims, on CLA, 16–17 CLA products GC–MS profile of unpatented and patented, 8 CognisGmbH, 5 Collagen, 102–105 characteristics of, 102 development of calorie-reduced products and, 103 used for fat reduction, 103 used in meat-producing industry, 102–103 water-binding capacity of, 103 COMT. See Catechol-O-methyltransferase (COMT) COMTL allele, 167–168 Conjugated linoleic acids (CLA) absorption and metabolism of, 5 application in functional foods, 17 body fat reduction by, 6–15 effect on body shape, 13

285 effects on body composition and body weight, 8–10 meta-analysis study, 14–15 overview, 6–7 quality of material used for, 7–8 carnitine palmitoyltransferase activity and, 6 chemical structure of isomers, 4 claims on, 15–16 and clinical studies on body composition, 10–15 exercise subjects with BMI less then 25, 12 long-term studies, 10–11 in subjects with BMI greater then 25, 12–13 in dairy products and ruminant meat, 4–5 efficacy in foods, 13–14 labeling of, 16 and lipoprotein lipase activity, 5–6 mechanism for decreasing body fat mass, 5–6 mixed isomers and safety evaluation, 15–16 overview, 3–5 regulatory status of, 16–17 sensory impact of, 19 stability of, 18–19 CPT activity. See Carnitine palmitoyltransferase (CPT) activity Critical Reviews in Food Science and Nutrition, 49 Cumulative incidence observational population-based prospective study (CARDIA), 77 Cyclic amino mono phosphate (cAMP), 168 Cyclin-dependent kinase 2 (CDK 2), 182–183 Dairy products cheese, 83 food application of, 82–84 nonfat dry milk, 83 overview, 68–69


22:45

286 Dairy products (Cont.) patent of, 84 scientific evidence on efficacy and mechanism of action of, 69–82 animal models and in vitro studies, 80–81 observational studies and secondary analyses of clinical trials, 75–80 randomized clinical trials, 69–75 summary of, 82 yogurt, 83 DEXA. See Dual energy X-ray absorptiometry (DEXA) d-fenfluramine, 110 Diet and Health: Implications for Reducing Chronic Disease Risk, 44 Dietary calcium effect on energy and substrate metabolism, 74 effects on body weight, 70–73 energy expenditure and consumption of, 73–75 food application of, 82–84 overview, 68–69 patent of, 84 scientific evidence on efficacy and mechanism of action of, 69–82 animal models and in vitro studies, 80–81 observational studies and secondary analyses of clinical trials, 75–80 randomized clinical trials, 69–75 summary of, 82 Dietary fiber alginate, 243 authoritative statements related to, 234–235 barley, 246 guar gum, 235–243 inulin, oligofructose, and polydextrose, 254–259 mechanism of actions, 233–234 oat β-glucan, 243–245 psyllium, 235 resistant starches, 259–265 soy fiber, oat hull fiber, and sugar beet fiber, 246–254 wheat and wheat bran, 246


Index Dietary proteins, satiating properties of, 113 Dieting versus lifestyle, 49–50 Digestibility, of RD, 218–219 Dual energy X-ray absorptiometry (DEXA), 9 EC. See Epicatechin (EC) ECG. See Epicatechin-3-gallate (ECG) EGC. See Epigallocatechin (EGC) EGCG. See Epigallocatechin-3-gallate (EGCG) EMS. See Eosinophilia-myalgia syndrome (EMS) Energy expenditure calcium and dairy foods consumption, 73–75 catechins and caffeine increase, 168–169 satiety of high-protein diet and increase in, 128 soy peptides reduces body weight by increasing, 143–144 Energy intake. See Caloric intake Eosinophilia-myalgia syndrome (EMS), 112 Epicatechin (EC), 179 Epicatechin-3-gallate (ECG), 179 Epigallocatechin (EGC), 179 Epigallocatechin-3-gallate (EGCG), 177 antiadipogenic effect of CDK 2 dependent signaling pathway, 182–183 via activation of AMPK, 183 via ERK dependent signaling pathway, 180–182 via regulation of ROS, 183–184 via resistin, 182 antiobesity mechanisms of, 180–187 inhibition of lipid-related enzymes in cell-free systems, 185 structures of, 179 ERK. See Extracellular signal-regulated kinase (ERK) Extracellular signal-regulated kinase (ERK), 180–182


22:45


Index FabulessTM . See Olibrar Fat-free mass (FFM), 60 influence of protein, ARG and LYS on, 129 Fat/oil replacement formulation matrix, of olestra, 51 Fecal excretion, calcium and dairy foods consumption, 73–75 Fermentation, of RD, 219 FFA. See Free fatty acids (FFA) FFM. See Fat-free mass (FFM) FI. See Food intake (FI) Food consumption, regulated by hypothalamus, 100 Food intake (FI). See also Caloric intake mechanism of action of soy peptides regulates, 137–141 olive oil placebo effects on, 33 PinnoThinTM effects on, 28–29, 33 ad libitum, 33–36 regulation by central nervous system, 229–233 long-term, 232–233 short-term, 229–232 serotonin in regulation of, 110 Four-compartment model, 9 Free fatty acids (FFA), 27 enzymatic hydrolysis of triglycerides into, 28 role in release of satiety hormones, 27–28 Functional foods, CLA application in, 17 Garcinia cambogia, 141 Gastric emptying, 230 GDH. See Glutamate dehydrogenase (GDH) Gelatin, 95–107 characteristics of, 102 collagenous peptides and, 102 dessert created by using, 104 raw material for, 101 technological properties of, 101–106 gelling properties, 105 used in meat-producing industry, 102–103

287 r mayonnaise, composition of, GELITA 104 r versus cheese product, 105 GELITA Ghrelin, 26 regulation of, 232 GLP-1. See Glucagon-like peptide-1 (GLP-1) Glucagon, 144 Glucagon-like peptide-1 (GLP-1), 26 effects on appetite, 27 Olibrar effects on, 59 regulation of FI and, 231 Glutamate dehydrogenase (GDH), 188 Glycemic response, of RD, 222–223 Glycomacropeptide (GMP), 123, 125 GMP. See Glycomacropeptide (GMP) Green tea, 178–179 antiadipogenic effect via downregulation of adipocyte marker proteins and its target genes, 186–187 via inhibition of lipogenic enzymes, 184–186 clinical studies of, 189–192 efficacy of long-term experiments for, 164–166 short-term experiments for, 162–163 epidemiological observation of, 189–192 food/supplement applications of, 170–171 global suppliers of, 171 insulin-potentiating activity by, 187–189 mechanisms of action of, 167–169 patent of, 171 safety of, 169–170 Guar gum, 235–243 studies reporting no significant effects of, 242 studies reporting positive effects of, 239–241 Gut hormones, related to satiety, 231

HDF. See Human diploid fibroblasts (HDF) HDL. See High-density lipoproteins (HDL)


22:45

288 High-density lipoproteins (HDL), 97 High-protein diet adverse effects of, 129–130 mechanisms to increase satiety of, 127–129 change in body composition, 128–129 changes in concentration of hormones/metabolites, 127–128 increase in energy expenditure, 128 during weight loss/maintenance, 122 Hormone-sensitive lipase (HSL), 168 HSL. See Hormone-sensitive lipase (HSL) 5-HTP. See 5-hydroxytryptophan (5-HTP) Human diploid fibroblasts (HDF), 184 Hunger. See also Satiety defined, 26 ratings after ingestion of α-lactalbumin, 114 Hydrodensitometry weighing, for body fat, 9 5-hydroxytryptamine. See Serotonin 5-hydroxytryptophan (5-HTP), 110, 112–113 Hypothalamus arcuate nucleus of, 229 food consumption regulated by, 100 serotonin role in regulation of appetite and food intake, 110 IGF-1. See Insulin-like growth factor-1 (IGF-1) Ileal brake, 230 Insulin-like growth factor-1 (IGF-1), 128 Insulin-potentiating activity, by green tea, 187–189 Insulin release, obesity and, 97–98 Insulin resistance syndrome (IRS), 76–77 Inulin, 254–259 studies reporting no significant effects of, 259 studies reporting positive effects of, 258 IRS. See Insulin resistance syndrome (IRS)


Index JNK. See c-Jun-N-terminal kinases (JNK) Labeling, of CLA, 16 Large neutral amino acids (LNAA), 111, 113 LDL. See Low-density lipoproteins (LDL) LDL-R transcription, by soybean, 142–143 Lifestyl versus dieting, 49–50 Lipid absorption, soy peptides reduces adiposity by inhibiting, 141–143 Lipid metabolism, soy peptides reduces adiposity by regulating, 141–143 Lipogenic enzymes, antiadipogenic effect of green tea, 184–186 Lipoprotein lipase (LPL) activity, 5–6 LNAA. See Large neutral amino acids (LNAA) Low-density lipoproteins (LDL), 97 LPL activity. See Lipoprotein lipase (LPL) activity l-tryptophan, 111–113 serotonin synthesized by, 110–111 LYS. See Lysine (LYS) Lysine (LYS), 129 MAPK. See Mitogen-activated protein kinases (MAPK) MCAD. See Medium-chain acyl-CoA dehydrogenase (MCAD) Medium-chain acyl-CoA dehydrogenase (MCAD), 169 Metabolic syndrome. See also Obesity defined, 98 therapeutic options for, 98–101 Metabolizable energy versus net metabolizable energy, 99–100 Mitogen-activated protein kinases (MAPK), 180 Monoglyceride, 28 Monounsaturated fatty acids (MUFA), 28 MUFA. See Monounsaturated fatty acids (MUFA) National Weight Control Registry, 49 Near-infrared interactance (NIR), 9 Net energy value (NEV), of RD, 219–220


22:45

Index Net metabolizable energy versus metabolizable energy, 99–100 NIR. See Near-infrared interactance (NIR) Nondialyzed soy protein hydrolysate (NSPH), 141–142 Nonfat dry milk, 83 No-observable adverse effect levels (NOAEL), of RD, 217 Norepinephrine (NE), 167 NSPH. See Nondialyzed soy protein hydrolysate (NSPH) r . See Resistant dextrin NUTRIOSE (RD) r FB, 216, 217 NUTRIOSE Nutrition, 96–97 Oat β-glucan, 243 studies reporting no significant effects of, 245 Oat fiber studies reporting no significant effects of, 255 Oat hull fiber, 246–254 Obesity. See also Metabolic syndrome adipocytes role in, 177–178 adipose tissue and, 97–98 analysis of, medical perspective, 97–98 olestra and, 47 weight maintenance for, 122 Obesity Reviews, 49 Olestra dieting versus lifestyle, 49–50 evolution of, 45–47 fat/oil replacement formulation matrix, 51 molecule, 46 potential food applications of, 50 role in cardiovascular and metabolic risk factors, 50–52 role in reducing fat-soluble environmental contaminants in body, 52 role in weight prevention, loss, and maintenance, 47–48 r Olibra constituents of, 56 efficacy of, 56–60


289 long-term experiments for, 58–60 short-term experiments for, 56–58 food/supplement applications of, 61–62 global suppliers of, 62 mechanisms of action, 61 patent, 62 safety aspect of, 61 Oligofructose (OF), 254–259 Olive oil placebo effects on CCK and GLP-1 release, 31 effects on food intake, 33 Oolong tea, insulin activity ratios in, 188 Peptide tyrosine tyrosine (PYY), 26 effects on appetite, 27 regulation of, 231–232 P&G. See Procter & Gamble Company (P&G) Phosphodiesterase, 168 Pine nut consumption, history of, 37 PinnoThinTM , 28 effects on in vitro CCK release, 29–30 effects on satiety and food intake, 28–29 food applications of, 36–37 and history of pine nut consumption, 37 unsaturated fatty acids found in, 29 in vivo effects on satiety hormones, 30–33 PinnoThinTM FFA effects on caloric intake, 35 effects on CCK and GLP-1 release, 31 effects on food intake, 33, 35 PinnoThinTM TG effects on CCK and GLP-1 release, 31 effects on food intake, 33 Pinus Koraiensis, 28 Polydextrose, 254–259 studies reporting effects of, 260 Polyunsaturated fatty acids (PUFA), 28 Preadipocyte factor-1 (pref-1), 145 increase by SPP and alcalase soy hydrolysates, 146 Preadipocytes, 145–146 Pref-1. See Preadipocyte factor-1 (pref-1) Procter & Gamble Company (P&G), 43, 45


22:45

290 Protein-based diet exerts, effects on weight loss, 99–100 Psyllium, 235 studies reporting no significant effects of, 238 studies reporting positive effects of, 236–237 PUFA. See Polyunsaturated fatty acids (PUFA) Pyruvate, 168 PYY. See Peptide tyrosine tyrosine (PYY) RD. See Resistant dextrin (RD) Reactive oxygen species (ROS), 183–184 REE. See Resting energy expenditure (REE) Regulatory status, of CLA, 16–17 Resistant dextrin (RD) body fat control in animals by, 222 caloric value, 219–220 digestibility of, 218–219 effects on satiety, 221–222 glycemic response and, 222–223 fermentation of, 219 overview, 215–216 safety of, 216–217 in humans, 217–218 Resistant starches (RS), 259–265 studies reporting no significant effects of, 263–264 studies reporting positive effects of, 261–262 Resistin (RSTN), 182 Resting energy expenditure (REE), 59–60 FFM and, 60 Resting metabolic rate (RMR), 12 RMR. See Resting metabolic rate (RMR) ROS. See Reactive oxygen species (ROS) RSTN. See Resistin (RSTN) Satiety. See also Hunger authoritative statements related to, 234–235 clinical methods for measuring, 228–229 definition of, 26, 227–228 gut hormones related to, 231


Index mechanisms to increase high-protein diet, 127–129 PinnoThinTM effects on, 28–29, 32 regulation by central nervous system, 229–233 side effects of, 129–130 Satiety hormones activity of, 26–27 effects on appetite, 27 FFA role in release of, 27–28 physiological factors affecting, 232–233 PinnoThinTM in vivo effects on, 30–33 Saturated fatty acids (SFA), 28 SBF. See Sugar beet fiber (SBF) SCFA. See Short-chain fatty acids (SCFA) Serotonin defined, 110 dietary amino acid interventions to increase precursor, 111–115 α-lactalbumin, 113–115 5-HTP, 112–113 l-tryptophan, 111–113 role in regulation of appetite and food intake, 110 synthesized by l-tryptophan, 110–111 SFA. See Saturated fatty acids (SFA) Short-chain fatty acids (SCFA), 218, 219, 233 SNS. See Sympathetic nerve system (SNS) Soy, 123 effects on satiety long-term, 126–127 short-term, 123–126 food supplement applications of, 130 global suppliers of, 130 patents on, 130 Soy fiber, 246–254 studies reporting no significant effects of, 256 Soy hydrolysate products inhibitory effects on preadipocyte proliferation, 145 Soy peptides antiobesity effects of, 138–139 dietary, 142 efficacy and mechanisms of action in weight control, 137–147


22:45


Index by increasing energy expenditure and thermogenesis, 143–144 by suppressing food intake, 137–141 food applications of, 147–148 global suppliers of, 149 role in reducing adiposity by inhibiting lipid absorption and regulation of lipid metabolism, 141–143 by inhibition of adipogenesis, 144–147 safety of, 148–149 Soy products, 150–151 Soy-purified peptides (SPP), 145 pref-1 increased by, 146 SPP. See Soy-purified peptides (SPP) STAT3 phosphorylation, 141 Substrate oxidation, calcium and dairy foods consumption, 73–75 Sugar beet fiber (SBF), 246–254 studies reporting no significant effects of, 257 Sympathetic nerve system (SNS), 167 capsaicin effects on thermogenesis, 206 Thermogenesis capsaicin increases, 206 soy peptides reduces body weight by increasing, 143–144 r CLA, 7 Tonalin Tonalin TG 80, chemical structure of CLA isomers of, 4 Total body electrical conductivity (TOBEC), 9 Transient receptor potential vanilloid receptor1 (TRPV1), 206 Triglycerides, enzymatic hydrolysis into FFA, 28 TRPV1. See Transient receptor potential vanilloid receptor1 (TRPV1) UCP. See Uncoupling proteins (UCP) Uncoupling proteins (UCP), 169 United States National Research Council, 44

291 Unsaturated fatty acids, found in PinnoThinTM , 29 VAS. See Visual analogue scales (VAS) Visual analogue scales (VAS), to evaluate appetite sensations, 31–33 Water-binding capacity, of collagen, 103 Weight control/maintenance capsaicin for, 207–208 high protein intake during, 122 for obesity, 122 olestra and, 47–48 Olibrar role in, 59 soy peptides in, 137–147 by suppressing food intake, 137–141 Weight loss caffeine role in, 166–167 dieting versus lifestyle, 49–50 high protein intake during, 122 olestra role in, 47–48 Olibrar role in, 60 protein-based diet exerts effects on, 99–100 Wheat, 246 studies reporting no significant effects of, 251 studies reporting positive effects of, 250 Wheat bran, 246 studies reporting no significant effects of, 253 studies reporting positive effects of, 252 Whey, 123 effects on satiety long-term, 126–127 short-term, 123–126 food supplement applications of, 130 global suppliers of, 130 patents on, 130 Yogurt, 83

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