1101
Exp Physiol 99.9 (2014) pp 1101–1103
Introduction Introduction
Experimental Physiology
Gut instinct: body weight homeostasis in health and obesity
Although it is popularly assumed that changes in body weight reflect the choices an individual makes about what food to eat, how much to eat and how much to exercise, the long-term balance between energy intake and energy output is mainly determined by unconscious physiological systems. The UK Department of Health Estimated Average Requirements for energy intake stipulate 2079 calories day−1 for women and 2605 for men (Scientific Advisory Committee on Nutrition, 2011). If, over a year, energy intake exceeds energy expenditure by merely 1% (20 calories day−1 for women, or about one banana per week), it will result in a gain of 2.6 kg in fat mass. This rate of weight gain will take a woman from normal weight to obesity in 10 years. The message is not that we should avoid eating bananas, but that despite large variations in both day-by-day food intake and voluntary energy expenditure, we generally have a near-miraculous ability to maintain a near-constant body weight over decades of life. This is ultimately because in humans, as in all mammals, energy intake and energy expenditure are tightly co-regulated by conserved neuronal and endocrine circuits. Obesity does not imply gluttony; gluttons might escape obesity and, conversely, obesity can arise from a perfectly ordinary level of food intake as the long-term result of a near-imperceptible imbalance in homeostatic mechanisms. Blaming the obese for their obesity is rather like blaming the poor for their poverty; they might be able to do something about their condition, but in practice it is often far from easy. Indeed, efforts to ‘cure themselves’ are often counterproductive; one of the strongest predictors of weight gain is weight-loss dieting. One of the largest studies to demonstrate this was The Growing Up Today Study (GUTS), a prospective study of >16,000 adolescents (Field et al. 2003). At the 3 year follow-up, adolescents who were frequent or infrequent dieters had gained significantly more weight than non-dieters. The strong evolutionary conservation of the mechanisms that regulate energy balance has meant that knowledge gained from animal models translates well into understanding of human physiology and behaviour; for example, mutations in genes that affect signalling in these pathways generally have very similar effects in rodents and humans. Two tightly conserved endocrine signals in particular have attracted massive attention. Ghrelin, secreted from the empty stomach, reaches maximal levels after a fast, and activates neurons in the arcuate nucleus of the hypothalamus that make two potent orexigens, neuropeptide Y (NPY) and agouti-related peptide (AgRP). Leptin, secreted by adipocytes, reports on the body’s fat reserves; it inhibits NPY/AgRP neurons, while activating others that express anorexigenic factors, notably neurons that express pro-opiomelanocortin (POMC). According to current dogma (supported by extensive evidence from many sources), POMC neurons and NPY/AgRP neurons are reciprocally linked, and which population is dominant determines how much (on average) an animal will eat. As an animal eats, neural and endocrine signals from the gut report on the volume ingested and on its composition, including its complement of fat, carbohydrates and protein. These signals converge on the ghrelin- and leptin-sensing circuits of the hypothalamus (Murphy & Bloom, 2006). These in turn project to other limbic sites, including the paraventricular nucleus, which is the primary regulator of the sympathetic nervous system and which also influences the pituitary–adrenal axis to regulate catabolic glucocorticoid secretion and the pituitary–thyroid axis to regulate metabolic rate. While this account is seductively simple, difficulties are arising from many different directions. First, a recent paper (MacFarlane et al. 2014) questions whether ghrelin (to date, the only
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
DOI: 10.1113/expphysiol.2014.081976
1102
Introduction
Exp Physiol 99.9 (2014) pp 1101–1103
known orexigenic hormone) has any physiological role in regulating energy balance. That paper adopted a classic ‘physiological’ approach and suggests that ghrelin affects food intake only at concentrations well in excess of those that are ever seen in physiological circumstances. Bariatric surgery is a very effective treatment for obesity in humans and, while this is far from an optimal intervention, understanding exactly why it is so effective may lead to new therapies that are more deliverable. The papers from Behary & Miras (2014) and le Roux & Bueter (2014) in this issue address this important area. It has been suggested that bariatric surgery might be effective in part through its consequences for ghrelin secretion. This has not been consistently supported by experimental evidence, but there are profound changes in the secretion of gut-derived anorexigenic hormones that seem likely to contribute, and which may provide leads for the development of pharmacological therapies for obesity. A particularly intriguing and important outcome of Roux-en-Y gastric bypass is an immediate improvement in glycaemia, and the mechanisms underlying this remain to be clarified fully. Second, the status of the POMC/NPY neurons as the primary neurons governing food intake has been disturbed by the demonstration that they are dominantly governed by a descending input from the paraventricular nucleus (Krashers et al. 2014). Indeed, some have argued that our conventional understanding of appetite regulation is inappropriately ‘hypothalamocentric’ and that regions of the caudal brainstem have been given relatively scant attention. The paper in this issue from Abraham et al. (2014) is a reminder that insulin also has an important role in energy balance and that its primary target may be in the dorsal vagal complex. Increasing attention is also now being given to both the hedonic pathways regulating food reward as targets for hormones (see Skibicka & Dickson, 2013) and to sensory pathways (see Spetter et al. 2014). Third, leptin is only one of many anorexogenic hormones and, while its levels correlate with fat mass, this correlation is quite weak; leptin concentrations may differ by 10-fold or more in individuals with the same body mass. Significant advances have been made in understanding the growth, function and regulation of adipose tissue, as the review from Boudina & Graham (2014) in this issue illustrates. However, there are still major gaps in our knowledge; 20 years after its discovery, we still know almost nothing about how leptin secretion is regulated. Animal studies and human genetics studies have also framed the contributions of genetic and epigenetic influences on body weight. Body weight in people is estimated (from twin studies) to be up to 80% heritable (Wardle et al. 2008), but an extensive search for the genes responsible has (so far) revealed associations that account for relatively little of the interindividual variation. This has focused attention on other heritable mechanisms and, in particular, on the consequences of events in uterine and early postnatal life. Notably, stress and impaired nutrition during gestation and in early postnatal life are now known to have lifelong ‘programming’ effects on physiology and metabolism. In mice, exposure to a maternal diet rich in sucrose leads to obesity and glucose intolerance in female offspring, and this is addressed in the paper by Samuelsson (2014) in this issue. Whether these effects are transmitted across generations remains to be established. The unfolding global obesity epidemic apparently reflects powerful interactions between genes and our changing environment. Although it seems likely that the key change in our environment is the increased availability of highly palatable, energy-dense food, there are many other environmental influences that may play a role. In those counties most affected to date, reduction in the cost of food has meant that the opportunity to become obese through overeating is now nearly universal. Our food is not only cheaper and tastier, it is also safer than ever; the prevalence of food-related infections has generally declined over recent decades, and the episodes of involuntary fasting that accompany minor infections are less common. The reduction in cigarette smoking is eliminating a potent anorexigen. Central heating is now nearly universal, and raised night-time ambient temperatures imply reduced involuntary energy expenditure. The increased consumption of high-fructose corn syrup, especially in drinks, is of particular concern in some countries, because there is evidence that fructose is more potently obesogenic than sucrose in rodents. Patterns of activity and food intake have also changed and, as touched on by the paper by Johnston (2014), the time of day alters lipid and glucose profiles following individual meals and, over a longer time scale, meal timing regulates adiposity and body weight. These changes may
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
Exp Physiol 99.9 (2014) pp 1101–1103
Introduction
1103
occur via the ability of timed feeding to synchronize local circadian rhythms in metabolically active tissues, including those in adipose tissue itself. Tempting though it is to blame fast food manufacturers, it is likely that many factors contribute to the increased prevalence of obesity. Meanwhile, there remains much to be done to understand the complex inter-relationship between appetite, metabolism, glucose hoemesostasis and adiposity and the various roles of diverse brain areas and multiple endocrine and neural pathways. In particular, we need a clearer understanding of those signals from the gastrointestinal tract that modulate both hedonic and homeostatic pathways. If we want public health policies to be informed by evidence rather than by ‘gut instinct’, perhaps we should begin by seeking to understand gut instinct better.
Gareth Leng Email: [email protected] References Abraham MA, Filippi BM, Kang GM, Kim MS & Lam TKT (2014). Insulin action in the hypothalamus and dorsal vagal complex. Exp Physiol 99, 1104–1109. Behary P & Miras AD (2014). Brain responses to food and weight loss. Exp Physiol 99, 1121–1127. Boudina S & Graham TE (2014). Mitochondrial function/dysfunction in white adipose tissue. Exp Physiol 99, 1168–1178. Field AE, Austin SB, Taylor CB, Malspeis S, Rosner B, Rockett HR, Gillman MW & Colditz GA (2003). Relation between dieting and weight change among preadolescents and adolescents. Pediatrics 112, 900–906. Johnston JD (2014). Physiological links between circadian rhythms, metabolism and nutrition. Exp Physiol 99, 1133–1137. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, Vong L, Pei H, Watabe-Uchida M, Uchida N, Liberles SD & Lowell BB (2014). An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242. McFarlane MR, Brown MS, Goldstein JL, Zhao TJ (2014). Induced ablation of ghrelin cells in adult mice does not decrease food intake, body weight, or response to high-fat diet. Cell Metab 20, 54–60. Murphy KG & Bloom SR (2006). Gut hormones and the regulation of energy homeostasis. Nature 444, 854–859. le Roux CW & Bueter M (2014). The physiology of altered eating behaviour after Roux-en-Y gastric bypass. Exp Physiol 99, 1128–1132. Samuelsson AM (2014). New perspectives on the origin of hypertension; the role of the hypothalamic melanocortin system. Exp Physiol 99, 1110–1115. Scientific Advisory Committee on Nutrition (2011). Dietary reference values for energy. https://www.gov.uk/government/uploads/ system/uploads/attachment_data/file/339317/SACN_Dietary_Reference_Values_for_Energy.pdf (accessed September 1 2014). Skibicka KP & Dickson SL (2013). Enteroendocrine hormones – central effects on behavior. Curr Opin Pharmacol 13, 977–982. Spetter MS, Mars M, Viergever MA, de Graaf C, Smeets PA (2014). Taste matters – effects of bypassing oral stimulation on hormone and appetite responses. Physiol Behav 137C, 9–17. Wardle J, Carnell S, Haworth CM & Plomin R (2008). Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr 87, 398–404.
Additional Information Competing interests None declared. Funding Appetite-related research in Gareth Leng’s laboratory is supported by European Commission Seventh Framework grants (FP7-KBBE-2010-4-266408, Full4Health; FP7-KBBE-2009-3-245009, NeuroFAST; and FP7/2007-2013 under Grant Agreement 607310, Nudge-it).
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
Exp Physiol 99.9 (2014) pp 1101–1103
Introduction Introduction
Experimental Physiology
Gut instinct: body weight homeostasis in health and obesity
Although it is popularly assumed that changes in body weight reflect the choices an individual makes about what food to eat, how much to eat and how much to exercise, the long-term balance between energy intake and energy output is mainly determined by unconscious physiological systems. The UK Department of Health Estimated Average Requirements for energy intake stipulate 2079 calories day−1 for women and 2605 for men (Scientific Advisory Committee on Nutrition, 2011). If, over a year, energy intake exceeds energy expenditure by merely 1% (20 calories day−1 for women, or about one banana per week), it will result in a gain of 2.6 kg in fat mass. This rate of weight gain will take a woman from normal weight to obesity in 10 years. The message is not that we should avoid eating bananas, but that despite large variations in both day-by-day food intake and voluntary energy expenditure, we generally have a near-miraculous ability to maintain a near-constant body weight over decades of life. This is ultimately because in humans, as in all mammals, energy intake and energy expenditure are tightly co-regulated by conserved neuronal and endocrine circuits. Obesity does not imply gluttony; gluttons might escape obesity and, conversely, obesity can arise from a perfectly ordinary level of food intake as the long-term result of a near-imperceptible imbalance in homeostatic mechanisms. Blaming the obese for their obesity is rather like blaming the poor for their poverty; they might be able to do something about their condition, but in practice it is often far from easy. Indeed, efforts to ‘cure themselves’ are often counterproductive; one of the strongest predictors of weight gain is weight-loss dieting. One of the largest studies to demonstrate this was The Growing Up Today Study (GUTS), a prospective study of >16,000 adolescents (Field et al. 2003). At the 3 year follow-up, adolescents who were frequent or infrequent dieters had gained significantly more weight than non-dieters. The strong evolutionary conservation of the mechanisms that regulate energy balance has meant that knowledge gained from animal models translates well into understanding of human physiology and behaviour; for example, mutations in genes that affect signalling in these pathways generally have very similar effects in rodents and humans. Two tightly conserved endocrine signals in particular have attracted massive attention. Ghrelin, secreted from the empty stomach, reaches maximal levels after a fast, and activates neurons in the arcuate nucleus of the hypothalamus that make two potent orexigens, neuropeptide Y (NPY) and agouti-related peptide (AgRP). Leptin, secreted by adipocytes, reports on the body’s fat reserves; it inhibits NPY/AgRP neurons, while activating others that express anorexigenic factors, notably neurons that express pro-opiomelanocortin (POMC). According to current dogma (supported by extensive evidence from many sources), POMC neurons and NPY/AgRP neurons are reciprocally linked, and which population is dominant determines how much (on average) an animal will eat. As an animal eats, neural and endocrine signals from the gut report on the volume ingested and on its composition, including its complement of fat, carbohydrates and protein. These signals converge on the ghrelin- and leptin-sensing circuits of the hypothalamus (Murphy & Bloom, 2006). These in turn project to other limbic sites, including the paraventricular nucleus, which is the primary regulator of the sympathetic nervous system and which also influences the pituitary–adrenal axis to regulate catabolic glucocorticoid secretion and the pituitary–thyroid axis to regulate metabolic rate. While this account is seductively simple, difficulties are arising from many different directions. First, a recent paper (MacFarlane et al. 2014) questions whether ghrelin (to date, the only
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
DOI: 10.1113/expphysiol.2014.081976
1102
Introduction
Exp Physiol 99.9 (2014) pp 1101–1103
known orexigenic hormone) has any physiological role in regulating energy balance. That paper adopted a classic ‘physiological’ approach and suggests that ghrelin affects food intake only at concentrations well in excess of those that are ever seen in physiological circumstances. Bariatric surgery is a very effective treatment for obesity in humans and, while this is far from an optimal intervention, understanding exactly why it is so effective may lead to new therapies that are more deliverable. The papers from Behary & Miras (2014) and le Roux & Bueter (2014) in this issue address this important area. It has been suggested that bariatric surgery might be effective in part through its consequences for ghrelin secretion. This has not been consistently supported by experimental evidence, but there are profound changes in the secretion of gut-derived anorexigenic hormones that seem likely to contribute, and which may provide leads for the development of pharmacological therapies for obesity. A particularly intriguing and important outcome of Roux-en-Y gastric bypass is an immediate improvement in glycaemia, and the mechanisms underlying this remain to be clarified fully. Second, the status of the POMC/NPY neurons as the primary neurons governing food intake has been disturbed by the demonstration that they are dominantly governed by a descending input from the paraventricular nucleus (Krashers et al. 2014). Indeed, some have argued that our conventional understanding of appetite regulation is inappropriately ‘hypothalamocentric’ and that regions of the caudal brainstem have been given relatively scant attention. The paper in this issue from Abraham et al. (2014) is a reminder that insulin also has an important role in energy balance and that its primary target may be in the dorsal vagal complex. Increasing attention is also now being given to both the hedonic pathways regulating food reward as targets for hormones (see Skibicka & Dickson, 2013) and to sensory pathways (see Spetter et al. 2014). Third, leptin is only one of many anorexogenic hormones and, while its levels correlate with fat mass, this correlation is quite weak; leptin concentrations may differ by 10-fold or more in individuals with the same body mass. Significant advances have been made in understanding the growth, function and regulation of adipose tissue, as the review from Boudina & Graham (2014) in this issue illustrates. However, there are still major gaps in our knowledge; 20 years after its discovery, we still know almost nothing about how leptin secretion is regulated. Animal studies and human genetics studies have also framed the contributions of genetic and epigenetic influences on body weight. Body weight in people is estimated (from twin studies) to be up to 80% heritable (Wardle et al. 2008), but an extensive search for the genes responsible has (so far) revealed associations that account for relatively little of the interindividual variation. This has focused attention on other heritable mechanisms and, in particular, on the consequences of events in uterine and early postnatal life. Notably, stress and impaired nutrition during gestation and in early postnatal life are now known to have lifelong ‘programming’ effects on physiology and metabolism. In mice, exposure to a maternal diet rich in sucrose leads to obesity and glucose intolerance in female offspring, and this is addressed in the paper by Samuelsson (2014) in this issue. Whether these effects are transmitted across generations remains to be established. The unfolding global obesity epidemic apparently reflects powerful interactions between genes and our changing environment. Although it seems likely that the key change in our environment is the increased availability of highly palatable, energy-dense food, there are many other environmental influences that may play a role. In those counties most affected to date, reduction in the cost of food has meant that the opportunity to become obese through overeating is now nearly universal. Our food is not only cheaper and tastier, it is also safer than ever; the prevalence of food-related infections has generally declined over recent decades, and the episodes of involuntary fasting that accompany minor infections are less common. The reduction in cigarette smoking is eliminating a potent anorexigen. Central heating is now nearly universal, and raised night-time ambient temperatures imply reduced involuntary energy expenditure. The increased consumption of high-fructose corn syrup, especially in drinks, is of particular concern in some countries, because there is evidence that fructose is more potently obesogenic than sucrose in rodents. Patterns of activity and food intake have also changed and, as touched on by the paper by Johnston (2014), the time of day alters lipid and glucose profiles following individual meals and, over a longer time scale, meal timing regulates adiposity and body weight. These changes may
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
Exp Physiol 99.9 (2014) pp 1101–1103
Introduction
1103
occur via the ability of timed feeding to synchronize local circadian rhythms in metabolically active tissues, including those in adipose tissue itself. Tempting though it is to blame fast food manufacturers, it is likely that many factors contribute to the increased prevalence of obesity. Meanwhile, there remains much to be done to understand the complex inter-relationship between appetite, metabolism, glucose hoemesostasis and adiposity and the various roles of diverse brain areas and multiple endocrine and neural pathways. In particular, we need a clearer understanding of those signals from the gastrointestinal tract that modulate both hedonic and homeostatic pathways. If we want public health policies to be informed by evidence rather than by ‘gut instinct’, perhaps we should begin by seeking to understand gut instinct better.
Gareth Leng Email: [email protected] References Abraham MA, Filippi BM, Kang GM, Kim MS & Lam TKT (2014). Insulin action in the hypothalamus and dorsal vagal complex. Exp Physiol 99, 1104–1109. Behary P & Miras AD (2014). Brain responses to food and weight loss. Exp Physiol 99, 1121–1127. Boudina S & Graham TE (2014). Mitochondrial function/dysfunction in white adipose tissue. Exp Physiol 99, 1168–1178. Field AE, Austin SB, Taylor CB, Malspeis S, Rosner B, Rockett HR, Gillman MW & Colditz GA (2003). Relation between dieting and weight change among preadolescents and adolescents. Pediatrics 112, 900–906. Johnston JD (2014). Physiological links between circadian rhythms, metabolism and nutrition. Exp Physiol 99, 1133–1137. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, Vong L, Pei H, Watabe-Uchida M, Uchida N, Liberles SD & Lowell BB (2014). An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242. McFarlane MR, Brown MS, Goldstein JL, Zhao TJ (2014). Induced ablation of ghrelin cells in adult mice does not decrease food intake, body weight, or response to high-fat diet. Cell Metab 20, 54–60. Murphy KG & Bloom SR (2006). Gut hormones and the regulation of energy homeostasis. Nature 444, 854–859. le Roux CW & Bueter M (2014). The physiology of altered eating behaviour after Roux-en-Y gastric bypass. Exp Physiol 99, 1128–1132. Samuelsson AM (2014). New perspectives on the origin of hypertension; the role of the hypothalamic melanocortin system. Exp Physiol 99, 1110–1115. Scientific Advisory Committee on Nutrition (2011). Dietary reference values for energy. https://www.gov.uk/government/uploads/ system/uploads/attachment_data/file/339317/SACN_Dietary_Reference_Values_for_Energy.pdf (accessed September 1 2014). Skibicka KP & Dickson SL (2013). Enteroendocrine hormones – central effects on behavior. Curr Opin Pharmacol 13, 977–982. Spetter MS, Mars M, Viergever MA, de Graaf C, Smeets PA (2014). Taste matters – effects of bypassing oral stimulation on hormone and appetite responses. Physiol Behav 137C, 9–17. Wardle J, Carnell S, Haworth CM & Plomin R (2008). Evidence for a strong genetic influence on childhood adiposity despite the force of the obesogenic environment. Am J Clin Nutr 87, 398–404.
Additional Information Competing interests None declared. Funding Appetite-related research in Gareth Leng’s laboratory is supported by European Commission Seventh Framework grants (FP7-KBBE-2010-4-266408, Full4Health; FP7-KBBE-2009-3-245009, NeuroFAST; and FP7/2007-2013 under Grant Agreement 607310, Nudge-it).
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
