Advances in Food and Nutrition Research

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VOLUME SEVENTY SIX

ADVANCES IN FOOD AND NUTRITION RESEARCH

ADVISORY BOARDS KEN BUCKLE University of New South Wales, Australia

MARY ELLEN CAMIRE University of Maine, USA

ROGER CLEMENS University of Southern California, USA

HILDEGARDE HEYMANN University of California, Davis, USA

ROBERT HUTKINS University of Nebraska, USA

RONALD JACKSON Brock University, Canada

HUUB LELIEVELD Global Harmonization Initiative, The Netherlands

DARYL B. LUND University of Wisconsin, USA

CONNIE WEAVER Purdue University, USA

RONALD WROLSTAD Oregon State University, USA

SERIES EDITORS GEORGE F. STEWART

(1948–1982)

EMIL M. MRAK

(1948–1987)

C. O. CHICHESTER

(1959–1988)

BERNARD S. SCHWEIGERT (1984–1988) JOHN E. KINSELLA

(1989–1993)

STEVE L. TAYLOR

(1995–2011)

JEYAKUMAR HENRY

(2011– )

VOLUME SEVENTY SIX

ADVANCES IN FOOD AND NUTRITION RESEARCH Edited by

JEYAKUMAR HENRY Singapore Institute for Clinical Sciences, Singapore, and Oxford Brookes University, UK

AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier

Academic Press is an imprint of Elsevier 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK 125 London Wall, London, EC2Y 5AS, UK First edition 2015 Copyright © 2015, Elsevier Inc. All Rights Reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-803606-8 ISSN: 1043-4526 For information on all Academic Press publications visit our website at http://store.elsevier.com/

CONTENTS Contributors Preface

vii ix

1. Capsaicin and Related Food Ingredients Reducing Body Fat Through the Activation of TRP and Brown Fat Thermogenesis

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Masayuki Saito 1. Introduction 2. Brown Adipose Tissue and Energy Expenditure 3. Brown Adipose Tissue in Humans 4. TRP-Mediated Activation and Recruitment of BAT 5. Antiobesity Food Ingredients Activating and Recruiting BAT 6. Conclusion and Perspective References

2. School-Based Interventions to Reduce Obesity Risk in Children in High- and Middle-Income Countries

2 3 6 11 16 20 20

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Charlotte E.L. Evans, Salwa Ali Albar, Elisa J. Vargas-Garcia, and Fei Xu 1. Introduction 2. High-Income Countries 3. Middle-Income Countries 4. Conclusions and Recommendations References

3. Digestion and Postprandial Metabolism in the Elderly

30 34 51 63 66

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Amber M. Milan and David Cameron-Smith 1. Introduction 2. Health and Disease in the Elderly 3. Nutrition, Food Consumption, and Health in the Elderly 4. Digestive Responses in the Elderly: Digestion and Absorption 5. Postprandial Metabolism in Aging 6. Conclusion References

80 80 82 85 100 109 109

v

Contents

vi

4. Gotu Kola (Centella asiatica): Nutritional Properties and Plausible 125 Health Benefits Udumalagala Gamage Chandrika and Peramune A.A.S. Prasad Kumara

1. Introduction 2. History of Gotu kola and Ancient Uses 3. Morphology and Distribution 4. Processing and Usage of Gotu Kola 5. Nutrient Composition 6. Phytonutrients 7. Analytical Techniques for Important Nutrient Compounds 8. Major Health Benefits of Gotu Kola 9. Toxicity and Safety 10. Gaps in the Knowledge and Future Directions for Research 11. Conclusion References Index

126 127 127 132 134 135 144 147 152 152 153 153 159

CONTRIBUTORS Salwa Ali Albar School of Food Science and Nutrition, King Abdul-Aziz University, PO Box 42807, 21551 Jeddah, Saudi Arabia, and Nutritional Epidemiology Group, School of Food Science and Nutrition, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK David Cameron-Smith Liggins Institute, University of Auckland, Auckland, New Zealand Udumalagala Gamage Chandrika Department of Biochemistry, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka Charlotte E.L. Evans Lecturer in Public Health Nutrition, Nutritional Epidemiology Group, School of Food Science and Nutrition, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK Peramune A.A.S. Prasad Kumara Department of Allied Health Sciences, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka

Amber M. Milan Liggins Institute, University of Auckland, Auckland, New Zealand Masayuki Saito Hokkaido University, Sapporo, Japan Elisa J. Vargas-Garcia Nutritional Epidemiology Group, School of Food Science and Nutrition, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK Fei Xu Nanjing Municipal Center for Disease Control and Prevention 2, Zizhulin, Nanjing 210003, China

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PREFACE Food remains a major passion in all our lives. It is an activity that we indulge in every single day. Over a lifetime, each of us would have tasted a thousand different foods and consumed a million phytochemicals and flavor molecules. Despite the regularity of food consumption, as a society we know so little about the foods we consume. Where does milk, eggs, meat, fish we eat come from? What agronomic and food technology practices were used to produce them? Obesity and under nutrition are stark reminders of our unequal society. The food industry is simultaneously seen as both the problem and the solution. How best can we engage with the food industry to develop foods to modulate appetite in the obese and develop low-cost nutritious foods for the undernourished? At the time of writing (2015), we are witnessing the largest movement of people the world has seen in decades. How efficiently can we feed them? What food security issues do we need to consider? The chapters in this volume, as always, reflect the global challenges of food and nutrition. It is also a sober reminder to the readers how pivotal a role food and nutrition plays in all our lives. C.J. HENRY Singapore and Oxford

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CHAPTER ONE

Capsaicin and Related Food Ingredients Reducing Body Fat Through the Activation of TRP and Brown Fat Thermogenesis Masayuki Saito1 Hokkaido University, Sapporo, Japan 1 Corresponding author: e-mail addresses: [email protected]; [email protected]

Contents 1. Introduction 2. Brown Adipose Tissue and Energy Expenditure 2.1 Mechanism of BAT Thermogenesis 2.2 Regulation of Brown/Beige Adipocytes 3. Brown Adipose Tissue in Humans 3.1 Human BAT Activated by Cold Exposure 3.2 BAT Thermogenesis and Obesity in Humans 4. TRP-Mediated Activation and Recruitment of BAT 4.1 TRP Channels as Cold- and Chemesthetic Receptors 4.2 BAT-Dependent Thermogenic Effect of Capsaicin and Capsinoids 4.3 Antiobesity Effect of Capsaicin and Capsinoids 5. Antiobesity Food Ingredients Activating and Recruiting BAT 5.1 Food Ingredients Activating the TRP-BAT Axis 5.2 Tea Catechins and Caffeine Activating BAT Thermogenesis 6. Conclusion and Perspective References

2 3 3 5 6 6 9 11 11 13 14 16 16 18 20 20

Abstract Brown adipose tissue (BAT) is a site of sympathetically activated adaptive nonshivering thermogenesis, thereby being involved in the regulation of energy balance and body fatness. Recent radionuclide imaging studies have revealed the existence of metabolically active BAT in adult humans. Human BAT is activated by acute cold exposure and contributes to cold-induced increase in whole-body energy expenditure. The metabolic activity of BAT is lower in older and obese individuals. The inverse relationship between the BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. In fact, repeated cold exposure recruits BAT in association with increased energy expenditure and decreased body

Advances in Food and Nutrition Research, Volume 76 ISSN 1043-4526 http://dx.doi.org/10.1016/bs.afnr.2015.07.002

#

2015 Elsevier Inc. All rights reserved.

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Masayuki Saito

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fatness. The stimulatory effects of cold are mediated through the activation of transient receptor potential (TRP) channels, most of which are also chemesthetic receptors for various naturally occurring substances including herbal plants and food ingredients. Capsaicin and its analog capsinoids, representative agonists of TRPV1, mimic the effects of cold to decrease body fatness through the activation and recruitment of BAT. The well-known antiobesity effect of green tea catechins is also attributable to the activation of the sympathetic nerve and BAT system. Thus, BAT is a promising target for combating obesity and related metabolic disorders in humans.

ABBREVIATIONS βAR β-adrenoceptor BAT brown adipose tissue CIT cold-induced thermogenesis COMT catechol-O-methyltransferase CT computed tomography EE energy expenditure FDG fluorodeoxyglucose GP Grains of Paradise PET positron emission tomography TRP transient receptor potential UCP1 uncoupling protein 1 WAT white adipose tissue

1. INTRODUCTION We are now facing a worldwide increase in obesity and associated metabolic disorders such as diabetes mellitus, hypertension, and dyslipidemia. As obesity is a result of prolonged imbalance between energy intake and energy expenditure (EE), it can be treated by reducing energy intake and/or increasing EE. For the latter, while increasing physical activity is usually recommended, but sustained change in physical activity is rather difficult to achieve in our daily life. Alternatively, search has been focusing on thermogenic natural products, particularly on specific food ingredients. Typical examples are capsaicin and its analogs in hot peppers, and caffeine and catechins rich in green tea, all of which have been reported to increase EE and fat oxidation and thereby may be effective for body fat loss (Dulloo, 2011; Hursel & Westerterp-Plantenga, 2010). Brown adipose tissue (BAT) is known as a site of sympathetically activated nonshivering thermogenesis during cold exposure and after spontaneous hyperphagia, thereby controlling whole-body EE and body fatness (Cannon & Nedergaard, 2004; Kajimura & Saito, 2014). This specific

Food Ingredients Activating Brown Fat Thermogenesis

3

thermogenic organ has currently drawn increasing attention as a therapeutic target to treat human obesity and related metabolic disorders (Lee, Swarbrick, & Ho, 2013; Ravussin & Galgani, 2011; Saito, 2013). This is because of several remarkable advancements in the field of BAT research over a last decade. First, being against the conventional view that BAT is of minute amounts and plays negligible roles in adult humans, radionuclide imaging studies have revealed the presence of considerable amounts of BAT in adult humans (Cypess et al., 2009; Nedergaard, Bengtsson, & Cannon, 2007; Saito et al., 2009; van Marken Lichtenbelt et al., 2009; Virtanen et al., 2009). Second, cellular and molecular analyses of brown adipose tissue and white adipose tissue (WAT) have revealed the presence of a new type of thermogenic adipocytes, termed “beige” or “brite” cells, which are developmentally distinct from “classical” brown adipocytes (Harms & Seale, 2013; Wu, Cohen, & Spiegelman, 2013). Lastly, studies in rodent models and also humans have suggested significant roles of BAT in the regulation of whole-body insulin sensitivity and glucose metabolism, in addition to thermogenesis (Chondronikola et al., 2014; Lee, Smith, et al., 2014; Nishio et al., 2012; Stanford et al., 2013). Thus, BAT is a promising target of some food ingredients for the treatment of obesity and related metabolic disorders. Here, I summarize recent evidence for the role of BAT in the regulation of EE and body fatness, with special references to the thermogenic and fat-reducing effects of some food ingredients in humans.

2. BROWN ADIPOSE TISSUE AND ENERGY EXPENDITURE 2.1 Mechanism of BAT Thermogenesis BAT is a unique adipose tissue, of which function is metabolic thermogenesis to produce energy in the form of heat (Cannon & Nedergaard, 2004). Significant amounts of BAT are found in small rodents and hibernators, being essential for the survival in cold environment and for arousal from hibernation. In these animals, BAT is the major site of adaptive thermogenesis after cold exposure (cold-induced nonshivering thermogenesis) and food intake (diet-induced thermogenesis). Adaptive thermogenesis is a significant component of whole-body EE, thereby being involved in the regulation of body fatness. This is supported by various lines of observation, particularly, that mice with genetically ablated BAT show decreased EE and diet-induced obesity (Enerba¨ck et al., 1997; Feldmann, Golozoubova, Cannon, & Nedergaard, 2009; Kontani et al., 2005), and that activation and recruitment of BAT by various physiological and

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pharmacological stimuli result in consistent reduction of body fatness (Inokuma et al., 2006; Lowell & Spiegelman, 2000; Rothwell & Stock, 1979). Thus, it is undoubted, at least in small rodents, that impaired thermogenesis by BAT is one of the causes of obesity. BAT thermogenesis is totally dependent on uncoupling protein 1 (UCP1), which is expressed selectively in mitochondria of brown adipocyte, but not in other types of cell including white adipocyte. UCP1 has the activity to uncouple oxidative phosphorylation from ATP synthesis, thereby dissipating energy as heat. UCP1-dependent BAT thermogenesis is directly regulated by sympathetic nerves distributed abundantly to this tissue: that is, noradrenaline released from the sympathetic nerve endings stimulates the β-adrenoceptor (βAR) signaling cascade, leading hydrolysis of intracellular triglyceride by activating hormone-sensitive and adipose triglyceride lipases (Fig. 1). The released fatty acids activate UCP1 and are oxidized in mitochondria to serve as an energy source of thermogenesis. Fatty acids from blood circulation are also used under some physiological conditions. While the principal substrate for BAT thermogenesis is fatty acids, glucose utilization is also enhanced greatly in parallel with UCP1 activation, probably for sufficient supply of oxaloacetate to enable rapid oxidation of fatty acids and acetyl CoA, and also for recovery of cellular ATP levels by activating anaerobic glycolysis (Inokuma et al., 2005). Thus, UCP1-dependent glucose utilization is a metabolic index of BAT thermogenesis and has been applied for assessing human BAT as noted in Section 3.1. There are two types of UCP1-positive thermogenic adipocyte (Harms & Seale, 2013; Kajimura & Saito, 2014; Wu et al., 2013). The major BAT depot in small rodents is found in the interscapular region. Adipocytes in this depot originate from Myf5-positive myoblastic cells that also give rise to skeletal muscle cells and are called “classical brown adipocytes.” UCP1-expressing adipocytes also develop in fat depots usually considered as WAT after prolonged cold exposure or repeated administration of sympathomimetics including β3AR agonists (Cinti, 2009; Guerra, Koza, Yamashita, Walsh, & Kozak, 1998; Nagase et al., 1996; Petrovic et al., 2010; Walde´n, Hansen, Timmons, Cannon, & Nedergaard, 2012; Wu et al., 2012). These adipocytes, named “beige or brite adipocytes,” arise from developmentally distinct lineages from classical brown adipocytes; they originate from a Myf5-negative precursor cells (Harms & Seale, 2013). Recent studies have indicated that beige/brite adipocytes have comparable thermogenic activities to classical brown adipocytes and contribute significantly to the regulation of body fatness (Okamatsu-Ogura et al., 2013; Shabalina et al., 2013).

Food Ingredients Activating Brown Fat Thermogenesis

5

Cold

TRP

Sympathetic nerve Noradrenaline

βAR AC

βAR

βAR

TG

βAR

cAMP HSL

UCP1

PKA ATGL

TG UCP1

UCP1

ATP

FA UCP1

White

Beige/brite

Brown

Glucose

FA, LP Heat

Body fat

Energy expenditure

Figure 1 Sympathetically activated thermogenesis in brown adipose tissue, lipid mobilization from white adipose tissue, and induction of beige adipocyte. Sympathetic nerve activity in adipose tissues is increased in response to cold exposure through the activation of transient receptor potential (TRP) channels. Noradrenaline binds to β-adrenergic receptors (βAR) and initiates the signaling cascade for triglyceride (TG) hydrolysis. Released fatty acids (FA) activate uncoupling protein 1 (UCP1) and are oxidized to serve as an energy source of thermogenesis. Chronic sympathetic activation produces not only brown fat hyperplasia but also an induction of beige adipocytes in white fat, thereby increasing whole-body energy expenditure and decreasing body fat. AC, adenylate cyclase; ATGL, adipose triglyceride lipase; cAMP, cyclic AMP; HSL, hormone-sensitive lipase; LP, lipoprotein; PKA, cAMP-dependent protein kinase.

2.2 Regulation of Brown/Beige Adipocytes As briefly summarized above, the sympathetic nerve and βAR system is a central regulator of brown and beige/brite adipocytes. This system is activated by various external stimuli, the most typical of which is cold exposure. The principal role of this system for BAT thermogenesis was confirmed by a finding that mice lacking βAR as well as those lacking UCP1 are unable to maintain body temperature under cold environments and die in couple of hours (Bachman et al., 2002; Enerba¨ck et al., 1997). It is also known that prolonged cold exposure or repeated administration of βAR agonists causes hyperplasia of BAT by increased proliferation of classical brown adipocyte and also induction of beige adipocytes in WAT (Guerra et al., 1998; Okamatsu-Ogura et al., 2013).

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In addition to or in combination with this system, some hormones and factors have been identified as activators/recruiters of BAT (Saito, 2014; Villarroya & Vidal-Puig, 2013). A representative is triiodothyronine (T3), which is well known as a potent transcriptional activator of the UCP1 gene (Bianco & McAninch, 2013). It is to be noted that T3 in BAT is produced from thyroxine by the action of type II deiodinase (D2), which is activated in response to sympathetic stimulation. D2 in BAT is also shown to be activated by bile acids coming from the liver (Watanabe et al., 2006). There have been reports demonstrating significant roles of heart-derived natriuretic peptides (NP), well-known regulators of fluid and hemodynamic homeostasis, in BAT recruitment. NP enhances whole-body EE, probably due to an upregulation of UCP1 in BAT and induction of WAT browning via the cyclic GMP and p38MAP-kinase signaling cascade (Collins, 2014). This cascade is also activated by nitric oxide, which is produced from arginine and also nitrate rich in green vegetables. Currently, much attention has been paid on the roles of macrophage in WAT browning. Qiu et al. (2014) reported that functional beige adipocytes are induced by noradrenaline released from macrophages that are alternatively activated by eosinophils. Critical roles of eosinophils and type 2 cytokine signaling in macrophage were also shown in the action of meterorinlike, a circulating factor induced in muscle after exercise and in adipose tissue upon cold exposure, which stimulates WAT browning and EE (Rao et al., 2014). The involvement of alternative activation of macrophages in the induction of thermogenic beige fat is a quite contrast with that of classical activation of macrophages, which is closely associated with metabolic and endocrine disorders of WAT. It is also known that fibroblast growth factor 21, a liver-derived endocrine factor, is potential for inducing the thermogenic program in BAT and WAT browning and also for reducing body fatness (Fisher et al., 2012). Thus, the activation of these humoral mechanisms by some food ingredients would enhance, additively to and/or synergistically with the sympathetic nerve-βAR system, BAT thermogenesis and reduce body fat.

3. BROWN ADIPOSE TISSUE IN HUMANS 3.1 Human BAT Activated by Cold Exposure Most information about BAT mentioned above has come from studies using small rodents such as mice, rats, and hamsters. In larger mammals including humans, anatomical and histological studies have reported that BAT is

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present only in neonates, but disappears rapidly during postnatal periods (Heaton, 1972). However, the existence of metabolically active BAT in adult humans was demonstrated by the studies using fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with computed tomography (CT): that is, FDG-PET/CT sometimes detects symmetrical FDG uptake in adipose tissue at the shoulder and thoracic spine regions (Cypess et al., 2009; Saito et al., 2009; van Marken Lichtenbelt et al., 2009; Virtanen et al., 2009). Such FDG uptake is greatly increased after cold exposure or administration of βAR agonists (Cypess et al., 2015; Kajimura & Saito, 2014), but reduced under warm conditions or by pretreatment with a β-adrenergic blocker (Fig. 2; Nedergaard et al., 2007). As β-adrenergically stimulated 2-deoxyglucose uptake into BAT is totally dependent on the activation of UCP1 (Inokuma et al., 2005), the observations by FDG-PET/CT suggest that the FDG uptake in adipose tissue at the specific regions reflects the metabolic activity of BAT. In fact, histological examinations revealed the presence of UCP1-positive adipocytes in these regions (Cypess et al., 2009; Saito et al., 2009; van Marken Lichtenbelt et al., 2009; Virtanen et al., 2009). Expression analysis of some marker genes has shown that BAT in the shoulder region of adult humans is largely composed of beige adipocytes more than classical brown adipocytes (Lee, Werner, Kebebew, & Celi, 2014; FDG uptake into BAT

Thermogenesis

Low

High

Low

High

Temperature

Warm

Cold

Season

Summer

Winter

β-Adrenoceptor

Antagonist

Agonist

Age

Old

Young

Fatness

Obese

Lean

Figure 2 Radionuclide imaging of human brown adipose tissue and influencing factors. Fluorodeoxyglucose (FDG) uptake into brown adipose tissue (BAT) at the supraclavicular and paraspinal regions is detected by positron emission tomography. BAT activity is influenced by various external and internal factors.

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Lidell et al., 2013; Sharp et al., 2012; Wu et al., 2012). Thus, the maximal activity of human BAT can be assessed by FDG-PET/CT after acute cold exposure at 16–19 °C for 1–2 h with light clothing. It is to be stressed that such mild cold exposure produces neither muscle shivering (Cypess, Haft, Laughlin, & Hu, 2014) nor changes in FDG uptake into other tissues including skeletal muscle (Nishio et al., 2012; Orava et al., 2011). The activity and prevalence of BAT detected by FDG-PET/CT in adults are influenced by various exogenous and endogenous factors (Fig. 2). The prevalence is less than 10% in most retrospective clinical studies, whereas it is 30–100% in dedicated studies for healthy volunteers (Kajimura & Saito, 2014; Lee et al., 2013). Such apparent discrepancy is largely due to the different temperatures at the FDG-PET/CT scanning: in dedicated studies, it is performed after acute cold exposure as noted above, whereas retrospective studies are mostly performed at room temperatures (22–26 °C) without cold exposure. Acute cold exposure increases FDG uptake into BAT, giving a high prevalence of BAT detection. Indeed, no BAT signals were detected at 27–28 °C even in subjects who showed high BAT activities after cold exposure. Moreover, the prevalence and activity of BAT are also influenced by outdoor temperature and show seasonal variations, being higher in winter than in summer even in the same subjects (Saito et al., 2009). This suggests that human BAT is a reversibly convertible tissue: in other words, it is inducible by environmental stimuli such as daily cold exposure. In fact, as mentioned in Section 3.2, repeated cold exposure induces BAT in subjects who have undetectable BAT before the cold exposure (Lee, Smith, et al., 2014; van der Lans et al., 2013; Yoneshiro, Aita, et al., 2013). The prevalence and activity of BAT are substantially modulated with age. Our study for healthy participants demonstrated that the prevalence of cold-activated BAT was more than 50% in young subjects of the twenties, decreased with age, and in less than 10% of the fifties and sixties (Matsushita et al., 2014; Yoneshiro, Aita, Matsushita, Okamatsu-Ogura, et al., 2011). A strong impact of age on BAT prevalence has also been reported in clinical studies (Persichetti et al., 2013; Pfannenberg et al., 2010; Quellet et al., 2011; Zhang et al., 2013). We found that polymorphism of some genes including UCP1 and β3AR accelerates the age-related decrease in BAT activity (Yoneshiro, Ogawa, et al., 2013). Recently, Bakker et al. (2014) reported larger BAT volume in healthy lean Caucasians than age-matched south Asians. These findings indicate a significant impact of genetic factors on human BAT, being consistent with a finding in mice that the induction of beige adipocyte is under genetic control (Guerra et al., 1998).

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3.2 BAT Thermogenesis and Obesity in Humans The presence of cold-activated BAT suggests a contribution of BAT to coldinduced thermogenesis (CIT) in humans as well as small rodents. In fact, it has been confirmed that whole-body EE estimated after mild cold exposure is greater in individuals with higher BAT activities (Muzik et al., 2013; Orava et al., 2011; Ouellet et al., 2012; van der Lans et al., 2013; Yoneshiro, Aita, Matsushita, Kameya, et al., 2011; Yoneshiro, Aita, et al., 2013). The BAT activity is positively correlated to CIT calculated from EE before and after cold exposure, indicating a significant role of BAT in cold-induced nonshivering thermogenesis. Moreover, FDG uptake into BAT was reported to increase after food intake (Vosselman et al., 2013). We also found that EE increased after an oral ingestion of food more in subjects with higher BAT activities, particularly during the initial period of 1 h (Saito, Aita, & Yoneshiro, 2011). Thus, it is highly likely that BAT is one of the sites for adaptive thermogenesis, and thereby contributes to the autonomic regulation of whole-body EE in humans, as it does in small rodents. This is supported by some previous studies examining the effects of UCP1 gene polymorphism. In the human UCP1 gene, there is a single nucleotide substitution at 3826 A to G (Oppert et al., 1994), which lowers UCP1 mRNA expression (Esterbauer et al., 1998), accelerates the age-related reduction of BAT prevalence (Rose et al., 2011; Yoneshiro, Ogawa, et al., 2013), and attenuates cold- and diet-induced thermogenesis (Nagai et al., 2007; Nagai, Sakane, Ueno, Hamada, & Moritani, 2003). Consistent with the significant role of BAT in short-term regulation of EE, there have been piles of evidence for BAT as a long-term regulator of energy balance and body fat content in humans. Both clinical and experimental studies have repeatedly shown significant inverse relationships between the activity/prevalence of BAT and adiposity-related parameters such as BMI, body fat content, and visceral fat accumulation. Retrospective readings of FDG-PET/CT in thousands of patients have revealed that BAT prevalence is lower in patients with higher BMI (Persichetti et al., 2013; Pfannenberg et al., 2010; Quellet et al., 2011; Zhang et al., 2013). Prospective studies in healthy participants also demonstrated that the prevalence and activity of cold-activated BAT decreased with increasing adiposity (Matsushita et al., 2014; van Marken Lichtenbelt et al., 2009; Yoneshiro, Aita, Matsushita, Okamatsu-Ogura, et al., 2011). The apparent association between BAT prevalence and adiposity, however, is to be carefully evaluated, because these are considerably influenced by age: that is, the activity/

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prevalence of BAT decrease with age as noted in Section 3.1, while body fatness increases with age, suggesting that age-related accumulation of body fat is associated with decreased BAT activity (Fig. 3). This is supported by the findings that the body fatness increases with age in the BAT-negative group, while it remained unchanged in the BAT-positive group (Yoneshiro, Aita, Matsushita, Okamatsu-Ogura, et al., 2011). Thus, it is conceivable that BAT, because of its energy dissipating activity, is protective against body fat accumulation in humans as it is in small rodents. This has encouraged the search how to activate or recruit BAT, which is particularly intriguing because people with lower or undetectable BAT activities are more obese and to be treated. As noted previously (Section 2.2), cold seems the most physiological and powerful stimulus for BAT activation. In addition to the acute stimulatory effects of cold on BAT, prolonged cold exposure produces not only BAT hyperplasia but also a remarkable induction of beige adipocytes, both of which give rise to an increase in EE and a reduction of body fatness in small rodents (Fig. 1). To extend this to humans, we examined the effects of repeated cold exposure in healthy volunteers with low or undetectable activities of BAT (Yoneshiro, Aita, et al., 2013). When they were exposed to cold at 17 °C for 2 h every day for 6 weeks, BAT activity assessed by FDG-PET/CT

Newborn

Old

Young Energy expenditure

Lean

Inactivation of BAT

Energy expenditure

Activation and recruitment of BAT Obese

Figure 3 Age-related decrease in brown adipose tissue and accumulation of body fat. The activity and prevalence of brown adipose tissue (BAT) decrease and body fat increases with age, suggesting the activation and recruitment of BAT as an effective regimen to prevent the age-related development of obesity.

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was increased. van der Lans et al. (2013) also reported increased BAT volume and activity in human adults placed in cold suits to acclimatize them to cold conditions a few hours a day for 10 days. These findings, being comparable with those in small rodents, confirm the recruitment of BAT after chronic cold exposure. More importantly, the change in BAT activity was positively and negatively correlated with those in CIT and body fat content, respectively (Yoneshiro, Aita, et al., 2013), suggesting a significant contribution of recruited BAT to body fat reduction.

4. TRP-MEDIATED ACTIVATION AND RECRUITMENT OF BAT 4.1 TRP Channels as Cold- and Chemesthetic Receptors Although repeated cold exposure can recruit human BAT, it would be difficult to increase exposure to cold in our daily life. It is now well established that cold stimulus is perceived by transient receptor potential (TRP) channels (Dhaka, Viswanath, & Patapoutian, 2006; Nakamura, 2011). TRP channels are nonselective cation channels with six putative transmembrane domains and a cation-permeable pore region. At present, more than 50 members of the TRP family are known in yeast, worms, insects, fish, and mammals, and serve as versatile sensors that allow individual cell and entire organisms to detect changes in their environment, such as temperature, touch, pain, osmolarity, taste, and other stimuli (Voets, Talavera, Owsianik, & Nilius, 2005). Particularly, most TRP channels are chemesthetic receptors for various naturally occurring substances including herbal plants and food ingredients (Table 1; Calixto, Kassuya, Andre, & Ferreira, 2005; Vriens, Nilius, & Vennekens, 2008). Capsaicin is the pungent principle in the fruits of Capsicum plants, commonly known as chili peppers, which are the mostly used in culinary preparations and also in traditional medicine for many centuries (Arora, Gill, Chauhan, & Rana, 2011). The primary action site of capsaicin is TPRV1 (TRP vanilloid receptor 1), which was cloned as a mammalian receptor for capsaicin (Caterina et al., 1997). The pungency of capsaicin is mediated through TRPV1 on sensory neurons in the oral cavity. TRPV1 is a calcium channel located on primary afferent neurons through the body, including the alimentary tract, and is activated by various kinds of stimuli such as noxious heat, proton, and compounds having a vanilloid moiety. Capsiate, the primary capsinoid in a nonpungent cultivar of red peppers, CH-19 Sweet, differs from capsaicin in chemical structure only at the center

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Table 1 Some TRP Channels and Herbal and Food-Related Agonistic Compounds Sensory TRP Channel Mediators Herbal and Food-Related Agonistic Compounds

TRPV1

Heat (>42 °C) Pungent spices Salt taste Acidosis Alkalosis Distension Chemical pain Chemesthesis

TRPM8

Cold (