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Clearly the globe has been urbanized; most countries have major urban centers, and many aspects of modern urban life are now found even in many small towns and villages e. In the same vein, globalization has brought vast shifts in access to modern food systems in terms of food shopping and away-from-home eating as well as wide exposure to food ads. Elsewhere I have presented in-depth some of the ways that globalization has affected the lives of individuals in the low- and middle-income world; these include ready access to modern supermarkets, rapid transmission of all the technologies that affect physical activity, and exposure to modern media 1,12, Global access to supermarkets is a cornerstone of changes in food distribution see also Chapter 30 by Christian and Gereffi, this volume.

We do not know exactly how the introduction of the Wal- Marts, Carrefours, Aholds, and many other global supermarkets is affecting dietary intake patterns in low-income countries, but we are sure that the changes are mixed some good and some bad. In the USA, changes in food distribution have followed a similar but more gradual course; we began with traditional supermarkets but have witnessed a sharp increase to The trend is toward increased dominance of the mass merchandisers In the lower-income world, the effects of this change are much more profound.

Fresh farmer, wet markets and small stores are disappearing, replaced increasingly by multinational, regional, and local large supermarkets usually part of larger chains like Carrefour or Wal-Mart or in countries such as South Africa and China by local chains that mimic Wal-Mart. China has all the global and huge local chains, whereas a smaller country like South Africa has its own domestically developed chain expanding across the urban areas of sub-Saharan Africa. Increasingly, large mega stores are found.

In one decade, the role of supermarkets in Latin America has expanded to be the equivalent of about a half-century of expansion in the USA. Supermarket use has spread across both large and small countries, from capital cities to rural villages, and from upper- and middle-class families to working- class families Eastern Europe, and Africa. The chains function to cut costs and improve efficiencies, and as major purchasers can bargain for lower prices and other economies with suppliers.

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Nevertheless, they provide access to a wide array of inexpensive, calorically dense, packaged foods that may promote weight gain in low-income as well as high-income populations. Consider India, where the bulk of retail outlets are still neighborhood shops. Carrefour, Wal-Mart, and others are spending billions to break into this market. But the growing middle class of India want these changes, want to shop more easily in air-conditioned comfort, and want many of the benefits in choice and variety that come from being part of a global food conglomerate The rate of increase in obesity has accelerated, particularly for children and adolescents.

The large-scale shifts in intake of calorically sweetened beverages, fried foods, and animal food products are striking, accompanied by powerful changes in patterns of eating. Concurrent trends toward reduced physical activity and increased sedentary behaviour have led to dramatic shifts in energy balance. The worldwide increases in intake of caloric sweeteners particularly sweetened beverages and the increased snacking and food consumption away-from-home are serious causes for concern. Popkin BM. The world is fat the fads, trends, policies, and products that are fattening the human race.

Nutrition program options for maternal and child health. Department of Health and Human Services. Better health for our children: a national strategy report of the select panel for the promotion of child health to the United States Congress and the Secretary of Health and Human Services. Washington, DC: U. Government Printing Office; Secular trends in childhood obesity in Denmark during 50 years in relation to economic growth.

Overweight exceeds underweight among women in most developing countries. Am J Clin Nutr. Epidemiological and nutritional transition in Mexico: rapid increase of non-communicable chronic diseases and obesity. Public Health Nutr. Nutrition transition in Mexico and in other Latin American countries. Nutr Rev. Rapid growth in infancy and childhood and obesity in later life a systematic review.

Obes Rev. Is there a lag globally in overweight trends for children as compared to adults? Trends of obesity and underweight in older children and adolescents in the United States, Brazil, China, and Russia. Obesity dynamics in China: The poor are catching up. Eur J Clin Nutr. Understanding Global Nutrition Dynamics as a step toward controlling cancer morbidity and mortality. Nat Rev Cancer. Establishing a standard definition for child overweight and obesity worldwide: international survey. Sobal J, Stunkard AJ.

Socioeconomic status and obesity: a review of the literature. Psychol Bull. Increasing disparity in knowledge of cardiovascular disease risk factors and risk-reduction strategies by socioeconomic status: implications for policymakers. Am J Prev Med. Socioeconomic status and health in blacks and whites: the problem of residual confounding and the resiliency of race.

Inequality in the built environment underlies key health disparities in physical activity and obesity. J Psychosom Res. Wang Y, Beydoun MA. Epidemiol Rev. The relationship of ethnicity, socioeconomic factors, and overweight in US adolescents.

Pediatric Obesity : Etiology, Pathogenesis, and Treatment

Obes Res. Wang Y. Cross-national comparison of childhood obesity: the epidemic and the relationship between obesity and socioeconomic status. Int J Epidemiol. The sweetening of the worlds diet. High-fructose corn syrup: is this whats for dinner? Evidence to support a food-based dietary guideline on sugar consumption in South Africa.

Bull World Health Organ. Energy from beverages is on the rise among Mexican adolescents and adults. J Nutr. Consumo de bebidas para una vida saludable: recomendaciones para la poblacin Beverage consumption for a healthy life: recommendations for the Mexican population. Salud Publica Mex. Changes in beverage intake between and Secular trends in childrens sweetened-beverage consumption to : The Bogalusa Heart Study. J Am Diet Assoc. Association of key foods and beverages with obesity in Australian schoolchildren. Drewnowski A, Popkin BM.

The nutrition transition: new trends in the global diet. Popkin B, Drewnowski A. Dietary fats and the nutrition transition: New trends in the global diet. Food and Agricultural Organization of the United Nations. Livestocks long shadow: environmental issues and options. Delgado CL. A food revolution: rising consumption of meat and milk in developing countries. The increasing prevalence of snacking among US children from to J Pediatr. Trends in food locations and sources among adolescents and young adults.

Prev Med. Trends in energy intake in U. Significant increase in young adults snacking between and represents a cause for concern!


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Dynamic shifts in Chinese eating behaviors. Asia Pac J Clin Nutr. Snacking patterns among adolescents: a comparison of type, frequency and portion size between Britain in and Northern Ireland in Br J Nutr. Small changes in snacking behaviour: the potential impact on CVD mortality. Body adiposity status in teenagers and snacking habits in early childhood in relation to approximal caries at 15 years of age. Int J Paediatr Dent. Food for thought or thought for food? Erlanson-Albertsson C, Zetterstrom R. The global obesity epidemic: snacking and obesity may start with free meals during infant feeding.

Acta Paediatr. Global Dynamics in Childhood Obesity Differential associations of fast food and restau- rant food consumption with 3-y change in body mass index: the Coronary Artery Risk Development in Young Adults Study. Body mass index gain, fast food, and physical activity: effects of shared environments over time. Obesity Silver Spring. Fast foods, energy density and obesity: a possible mechanistic link.

Fast food: unfriendly and unhealthy. Int J Obes. Fast food restaurant use among adolescents: asso- ciations with nutrient intake, food choices and behavioral and psychosocial variables. Are child eating patterns being transformed globally? Must A, Tybor DJ. Physical activity and sedentary behavior: a review of longitudinal studies of weight and adiposity in youth. Int J Obes Lond. Relationships between media use, body fatness and physical activity in children and youth: a meta-analysis.

Tracking of physical activity, fitness, body composition and diet from adolescence to young adulthood: the Young Hearts Project, Northern Ireland. Physical activity in overweight and nonoverweight preschool children. Objective physical activity of Filipino youth stratified for commuting mode to school.

Med Sci Sports Exerc. Physical activity and inactivity in Chinese school-aged youth: the China Health and Nutrition Survey. Omission of active commuting to school and the prevalence of childrens health-related physical activity levels: the Russian Longitudinal Monitoring Study. Child Care Health Dev. Active commuting to school: an overlooked source of childrens physical activity?

Sports Med. The impact of the Pathways intervention on psychosocial variables related to diet and physical activity in American Indian schoolchildren. Pathways: a school-based, randomized controlled trial for the prevention of obesity in American Indian schoolchildren. Objectively assessed associations between physical activity and body composition in middle-school girls: the Trial of Activity for Adolescent Girls.

Am J Epidemiol. Promoting physical activity in middle school girls: Trial of Activity for Adolescent Girls. Health Educ Res. Food and Nutrition Board. Preventing childhood obesity: health in the balance. Technology, transport, globalization and the nutrition transition. Food Policy.

Pediatric Obesity

Trager J. The food chronology: a food lovers compendium of events and anecdotes, from prehistory to the present. Reardon T, Berdegu J. The rapid rise of supermarkets in Latin America: challenges and opportunities for development. Dev Policy Rev. The rapid rise of supermarkets in developing countries: induced organizational, institutional, and technological change in agrifood systems. Electron J Agric Dev Econ. The rise of supermarkets in Africa, Asia, and Latin America. Am J Agric Econ. The emergence of supermarkets with Chinese characteristics: challenges and opportunities for Chinas agricultural development.

Wax E. In India, a retail revolution takes hold: small vendores feel squeeze of chaines. Washington Post. Robert H. Key Words: Leptin, hypothalamus, vagus, reward, stress, ghrelin, insulin, endocannabinoids, sympathetic nervous system, amygdala. Gluttony and sloth after all are two of the seven deadly sins. Obese adults and their children are assumed to have free choice with regard to food intake and energy expenditure and are therefore responsible for their metabolic fates 1.

But no child chooses to become obese; indeed the quality of life of an obese child is similar to that of children receiving cancer chemotherapy 2. Furthermore, the striking increases in obesity prevalence in 2- to 5-year-old children 3 suggest that there are other explanations for the obesity epidemic. The discovery of leptin in 4 revealed a complex neuroendocrine axis regulating energy bal- ance. Much of what we know about energy balance is derived from studies of animal models, but clinical studies provide invaluable insights. The homeostatic pathway of energy balance.

Afferent blue , central black , and efferent white pathways are delineated. The hormones insulin, leptin, ghrelin, and peptide YY PYY provide afferent information to the ventromedial hypothalamus regarding short-term energy metabolism and energy sufficiency. From there, the ventromedial hypothalamus elicits anorexigenic -melanocyte-stimulating hormone, cocaineamphetamine-regulated transcript and orexigenic neuropeptide Y, agouti-related protein signals to the melanocortin-4 receptor in the par- aventricular nucleus and lateral hypothalamic area. These lead to efferent output via the locus coeruleus and the nucleus tractus solitarius, which activate the sympathetic nervous system, causing the adipocyte to undergo lipolysis; or the dorsal motor nucleus of the vagus, which activates the vagus nerve to store energy, both by increasing pancreatic insulin secretion and in rodents by increasing adipose tissue sensitivity to insulin.

From Lustig Courtesy of Nature Publishing Group, with permission. The neuroendocrine axis is composed of three arms Fig. The first is the afferent arm, which conveys peripheral information on hunger and peripheral metabolism in the form of hormonal and neural inputs to the hypothalamus. The second is a central processing unit, consisting of various areas within the hypothalamus. Other brain areas serve as neuromodulators of this system.


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The third component is an efferent arm of autonomic effectors with origins in the locus coeruleus LC and dorsal motor nucleus of the vagus DMV , which regulate energy intake, expenditure, and storage 5,6. Anatomic disruptions or genetic or metabolic alterations of either the afferent, central processing, or efferent arms can alter energy intake or expenditure, leading to either obesity or cachexia.

There are three primary stimuli to eat: hunger, reward, and stress. While each of these internal phe- nomena infer altered behavior, each is actually mediated through a complex cascade of biochemicals that perturb the negative feedback pathway of energy balance and drive food intake in stereotypical patterns. The afferent vagus nerve conveys information regarding mechanical stretch of the stomach and duo- denum and feelings of gastric fullness to the nucleus tractus solitarius NTS 7.

Of note, the effects of alimentary neuropeptides below on hunger and satiety are obviated by concomitant vagotomy, implicating the afferent vagus as the primary mediator of alimentary energy balance signals Ghrelin: Ghrelin, an octanoylated amino acid peptide, was discovered serendipitously during a search for the endogenous ligand of the growth hormone secretagogue receptor GHS-R The endogenous secretion of ghrelin from the stomach is high during fasting and decreased by nutrient administration; volumetric stretching of the stomach wall has no effect.

Ghrelin also increases the respiratory quotient RQ in rats, suggesting a reduction of fat oxidation. Ghrelin appears to link the lipolytic effect of GH with hunger signals and is probably important in the acute response to fasting. In humans, ghrelin levels rise with increasing subjective hunger and peak at the time of voluntary food consumption 14 , suggesting that ghrelin acts on the VMH to trigger meal initiation. Ghrelin infusion increases food intake in humans However, plasma ghrelin levels are low in most obese individuals and increase with fasting 16 , suggesting that ghrelin is a response to, rather than a cause of, obesity.

The PraderWilli syndrome, an obesity disorder associated with hyperghrelinemia, may be a unique exception see Chapter 4 by Haqq, this volume. This peptide fragment is secreted by intestinal L-cells following exposure to nutrients; PYY crosses the bloodbrain barrier and binds to the Y2 receptor in the VMH. Although the pharmacology of this peptide is being elucidated, and agonists are being developed, its specific role in obesity is not yet known. GLP-1 acts on the stomach to inhibit gastric emptying; this increases the time available for absorp- tion of a meal.

Central regulation of leptin signaling, autonomic innervation of the adipocyte and -cell, and the starvation response. In leptin sufficiency, efferents from the hypothalamus synapse in the locus coeruleus, which stimulates the sympathetic ner- vous system. In leptin deficiency or resistance, efferents from the hypothalamus stimulate the dorsal motor nucleus of the vagus.

In leptin sufficiency, nore- pinephrine binds to the 3 -adrenergic receptor, which stimulates hormone-sensitive lipase, promoting lipolysis of stored triglyceride into free fatty acids. In leptin deficiency or resistance, vagal acetylcholine increases adipose tissue insulin sensitivity documented only in rats to date , promotes uptake of glucose and free fatty acids for lipogenesis, and promotes triglyceride uptake through activation of lipoprotein lipase. Glucose entering the cell is converted to glucosephosphate by the enzyme glucokinase, generating ATP, which closes an ATP-dependent potassium channel, resulting in cell depolarization.

A voltage-gated calcium channel opens, allowing for intracellular calcium influx, which activates neurosecretory mechanisms leading to insulin vesicular exocytosis. In leptin sufficiency, norepinephrine binds to 2 -adrenoceptors on the -cell membrane to stimulate inhibitory G proteins, decrease adenyl cyclase and its product cAMP, and thereby reduce protein kinase A levels and insulin release.

In leptin deficiency or resistance, the vagus stimulates insulin secretion Octreotide binds to a somatostatin receptor on the -cell, which is coupled to the voltage-gated calcium channel, limiting cal- cium influx and the amount of insulin released in response to glucose reprinted with kind permission of Springer Science and Business media. GLP-1 also stimulates -cell replication and increases -cell mass Metabolic Afferents Controlling Energy Balance Leptin: The balance of energy intake and expenditure is normally regulated very tightly within 0.

Leptin is a amino acid hormone produced by white adipocytes. Leptins primary neuroendocrine role is to mediate information about the size of periph- eral adipocyte energy stores to the VMH 4, As such, it is a prerequisite signal to the VMH for the initiation of high-energy processes such as puberty and pregnancy 22, Leptin reduces food intake and increases the activity of the sympathetic nervous system SNS Conversely, low leptin levels infer diminished energy stores, which impact on the VMH to increase food intake and reduce energy expenditure.

Serum leptin concentrations drop precipitously and to a greater degree than fat mass during short-term fasting 25,26 , and it seems likely that leptin functions more as a peripheral signal to the hypothalamus of inadequate caloric intake than as a hunger or satiety signal per se In the fed state, circulating levels of leptin correlate with percent body fat 28, Leptin produc- tion by adipocytes is stimulated by insulin and glucocorticoids 30,31 and inhibited by -adrenergic stimulation Programming of relative leptin concentrations by early caloric intake may be one mechanism that links early overnutrition with later obesity Leptin binds to its receptor a member of the Class 1 cytokine receptor superfamily on target VMH neurons.

There are four receptor isoforms formed by differential splicing: ObRa, an isoform with a shortened intracellular domain, which may function as a transporter; ObRb, the intact full-length receptor; ObRc, also with a short intracellular domain; and ObRe, which lacks an intracellular domain and functions as a soluble receptor As leptin binds to its VMH receptor, three neuronal signals are transduced.

The first is opening of an ATP-sensitive potassium channel, which hyperpolarizes the neuron and decreases its firing rate The second is the activation of a cytoplasmic Janus kinase 2 JAK2 , which phosphorylates a tyrosine moiety on proteins of a family called signal transduction and transcription STAT-3 The phosphorylated STAT-3 translocates to the nucleus, where it promotes leptin-dependent gene tran- scription Insulin: Insulin plays a critical role in energy balance In peripheral tissues it promotes glycogenesis, muscle protein synthesis, and fat storage and regulates the production and action of neuroendocrine modulators of nutrient uptake and metabolism.

But insulin is also transported across the bloodbrain barrier and binds to receptors in a subpopulation of VMH neurons 39,40 , suggesting that it acts centrally to regulate food intake. Indeed in animals, acute and chronic intracerebroven- tricular insulin infusions decrease feeding behavior and induce satiety The data on acute and chronic peripheral insulin infusions are less clear.

Studies of overinsulinized diabetic rats demon- strate increased caloric intake in order to prevent subacute hypoglycemia and the development of peripheral insulin resistance 44, Chronic peripheral insulin infusions in experimental animals decrease hepatic and skeletal muscle glucose uptake by reducing Glut4 expression but do not alter adipose tissue glucose uptake 46, One human study injecting short-term insulin peripherally dur- ing meals did not demonstrate an effect on satiety NIRKO mice become hyperphagic, obese, and infertile with age and have high peripheral insulin levels.

These findings suggest that peripheral insulin mediates a satiety signal in the VMH to help control energy balance Various knockouts of the insulin signal transduction pathway that reduce insulin signaling lead to an obese phenotype 52,53 , while those that increase insulin signaling lead to a lean phenotype 54, The ligand -melanocyte- stimulating hormone -MSH is the primary product involved in anorexigenesis. CART is a hypothalamic neuropeptide induced by leptin and reduced by fasting.

Intrahypothalamic infusion blocks appetite, while antagonism of endogenous CART increases caloric intake NPY has numerous functions within the hypothalamus, including initiation of feeding, puberty, and regulation of gonadotropin secretion and adrenal responsiveness 60, NPY is the primary orexigenic peptide. These actions are mediated through Y1 and Y5 receptors. AgRP is the human homolog of the protein agouti, which is present in abundance in the yellow y A -a mouse This protein is an endogenous competitive antagonist of all melanocortin receptors MCR , accounting for the yellow color in these mice.

The actions of NE on food intake seem paradoxical, as intrahypothalamic NE infusions stimulate food intake through effects on central 2 - and -adrenergic receptors 68 , whereas central infusion of 1 -agonists markedly reduces food intake Serotonin 5-HT : Five lines of evidence impicate a role for 5-HT in the perception of satiety: 1 Injection of 5-HT into the hypothalamus increases satiety, particularly with respect to carbohydrate 70 ; 2 central administration of 5-HT2c receptor agonists increases satiety, while antagonists induce feeding 71 ; 3 administration of selective 5-HT reuptake inhibitors induces early satiety 72 ; 4 leptin increases 5-HT turnover 73 ; and 5 the 5-HT2c R-KO mouse exhibits increased food intake and body weight The role of 5-HT in the transduction of the satiety signal may have both central and peripheral components, as intestinal 5-HT secreted into the bloodstream during a meal may impact GI neuronal function and muscle tone while binding to 5-HT receptors in the NTS see earlier to promote satiety MCH neurons synapse on neurons in the forebrain and the locus coeruleus.

MCH appears to be important in behavioral responses to food such as anxiety and aggression MCH knockout mice are hypophagic and lean 77 , while transgenic MCH-overexpressing mice develop obesity and insulin resistance Orexins A and B: These and amino acid peptides, respectively, have been implicated in both energy balance and autonomic function in mice Orexin knockout mice develop narcolepsy, hypophagia, and obesity 81 , suggesting that orexins bridge the gap between the afferent and efferent energy balance systems Orexins in the LHA stimulate neuropeptide Y NPY release, which may account for their induction of food intake; they also increase corticotropin-releasing factor CRF and sympathetic nervous system SNS output to promote wakefulness, energy expenditure, learning and memory, and the hedonic reward system see later Conversely, orexin neurons in the perifornical and dorsomedial hypothalamus regulate arousal and the response to stress.

Endocannabinoids ECs : It has long been known that marijuana and its major constituent tetrahy- drocannabinol stimulate food intake. Recently, endogenous ECs and the CB1 receptor have been linked to energy balance and the metabolic syndrome Fasting and feeding are associated with high and low levels of ECs in the hypothalamus, respectively. Glucocorticoids increase food intake in part by stimulating EC synthesis and secretion, while leptin blocks this effect These observations suggest that the MC4 R transduces satiety information on caloric suffi- ciency.

The role of the MC4 R in human obesity is well known; in some studies, 2. In the MC3 R knockout mouse, a different phenotype is seen. These animals are obese but hypophagic and have increased body fat relative to lean body mass. They gain weight on either low- or high-fat chow and do not change caloric oxidation in response to changes in dietary fat content. These findings suggest a defect in energy expenditure The role of the MC3 R in human obesity is less clear. Functional variants of the MC3 R have been noted in certain populations 88, Similarly, insulin administration acutely increases SNS activity in normal rats and in humans 93, The SNS increases energy expenditure by activating lipolysis in white and brown adipose tissue and promoting energy utilization in skeletal and cardiac muscle.

Binding of catecholamines to muscle 2 -adrenergic receptors 95 stimulates glycogenolysis, myocardial energy expenditure, and increases in glucose and fatty acid oxidation and increases protein synthesis 96, UCP1 is an inner membrane mitochondrial protein that uncouples proton entry from ATP syn- thesis ; therefore, UCP1 expression dissipates energy as heat and thereby reduces the energy efficiency of brown fat.

UCP1 is induced by FFAs derived from triglyceride breakdown; FFAs released from adipocytes are transported to the liver, where they are utilized for energy through ketogenesis. Lipolysis reduces leptin expression; thus a negative feedback loop is achieved between leptin and the SNS Fig. The efferent vagus opposes the SNS by promoting energy storage in four ways: a it reduces myocardial oxygen consumption by reducing heart rate; b it increases nutrient absorption by promoting GI peristalsis and pyloric opening; c it increases insulin sensitivity by potentiating the uptake of glucose and FFA into adipose tissue; and d it increases postprandial insulin secretion, which increases fat deposition Retrograde tracing of white adipose tissue reveals a wealth of efferents originating at the DMV These efferents synapse on M1 muscarinic receptors, which increase insulin sensitivity.

Thus, vagal modulation of the adipocyte augments storage of both glucose and FFAs by improving adipose insulin sensitivity and reducing triglyceride breakdown Fig. The DMV also sends efferent projections to the -cells of the pancreas This pathway is responsible for the cephalic or preabsorptive phase of insulin secretion, which is glucose inde- pendent and can be blocked by atropine Overactive vagal neurotransmission increases insulin secretion from -cells in response to an oral glucose load through three distinct but overlapping mech- anisms Fig.

Vagal induction of insulin secretion promotes lipogenesis through increased expression of Glut 4, acetyl-CoA carboxylase, fatty acid synthase, and lipoprotein lipase , The hedonic pathway comprises the ventral tegmental area VTA and the nucleus accumbens NA , with inputs from various components of the limbic system including the striatum, amygdala, hypothalamus, and hippocampus.

Food intake is a readout of the hedonic pathway; administration of morphine to the NA increases food intake in a dose-dependent fashion Functional suppression of the hedonic pathway curtails food intake when energy stores are replete; dysfunction or continuous activation of the hedonic pathway can increase food intake and promote excessive weight gain. The VTA appears to mediate feeding on the basis of palatability rather than energy need. The dopaminergic projection from the VTA to the NA mediates the motivating, rewarding, and reinforc- ing properties of various stimuli, such as food and addictive drugs.

Leptin and insulin receptors are expressed in the VTA, and both hormones have been implicated in modulating rewarding responses to food and other pleasurable stimuli For instance, fasting and food restriction when insulin and leptin levels are low increase the addictive properties of drugs of abuse, while central leptin admin- istration can reverse these effects Food deprivation in rodents increases addictive behavior and the pleasurable responses to a food reward, as measured by dopamine release and dopamine recep- tor signaling Conversely, insulin increases expression and activity of the dopamine transporter, which clears and removes dopamine from the synapse; thus acute insulin exposure blunts the reward of food Furthermore, insulin appears to inhibit the ability of VTA agonists e.

Finally, insulin blocks the ability of rats to form a conditioned place preference association to a palatable food The role of the hedonic pathway in human obesity is not yet elucidated, but can be surmised. This may explain in part the higher risk of obesity in patients taking drugs that block D2 recep- tors e. Alternatively, the down-regulation of dopaminergic activity in obese subjects may be an adaptive response to prior weight gain. Under normal circumstances, leptin and insulin signal adipose and nutrient sufficiency to the VTA, suppressing dopamine neurotransmission and the reward of food However, these negative feedback loops are blocked in states of insulin and leptin resistance that characterize obesity Positron emission tomography suggests that hunger and satiety neuronal circuits in the VMH con- nect with other regions of the limbic system that control primal emotions, reproductive activity, and survival instinct; a primal reward or pleasure response might explain ingestive behavior in the absence of hunger, a common finding in obese children and adults.

Encore -- Pediatric obesity : etiology, pathogenesis, and treatment / Michael Freemark, editor.

It has been argued that much of the impasse in efforts to both treat and prevent obesity stems from the intrinsic difficulty of overriding instinct with reason Stress hormones such as the glucocorticoids are essential for the full expression of obesity in rodents and humans and may explain the disruptive role that stress plays in weight regulation Stress and glucocorticoids are integral in promoting the constellation of features characteristic of the metabolic syndrome. Studies of adrenalectomized ADX rats supplemented with corticosterone demonstrate that exogenous fat intake is directly proportional to circulating corticosterone concen- trations , In intact rats, corticosterone stimulates intake of high-fat food; likewise, cortisol administration increases food intake in humans Human research shows increased caloric intake of comfort foods i.

Moreover, sev- eral studies in children have observed relationships between stress and unhealthy dietary practices, including increased snacking and an elevated risk of weight gain during adolescence and adulthood , NPY and catecholamines co-localize in sympathetic neurons in the peripheral nervous system as well as the central nervous system. In response to chronic stress, peripheral neurons express more NPY, which stimulates endothelial cell angiogenesis and preadipocyte proliferation, differentia- tion, and adipogenesis by activating Y2 receptors in visceral adipose tissue.

This causes abdominal obesity, inflammation, hyperlipidemia, hyperinsulinemia, glucose intolerance, hepatic steatosis, and hypertension, reproducing the features of the human metabolic syndrome. Conversely, local intra-fat Y2R antagonists or adenoviral Y2R knock-down reverses or prevents fat accumulation and metabolic complications This suggests that acute stress causes lipolysis and weight loss, but chronic stress hijacks the SNS, increasing NPY expression to cause visceral fat accumulation and metabolic dysfunction.

Everyone appears to have a personal leptin threshold, probably genetically determined, above which the brain interprets a state of energy sufficiency The leptin-replete fed state is characterized by increased physical activity, decreased appetite, and feelings of well-being. This is interpreted by the VMH as starvation. Gastric secretion of ghrelin increases; this stimulates pituitary GH release, which promotes lipolysis to provide energy substrate for catabolism.

The resultant lack of anorexigenic pressure on the MC4 R increases feeding behavior, reduces fat oxidation, and promotes fat deposition. Fat storage is facilitated by increases in insulin sensitivity. Total and resting energy expenditure decline in an attempt to conserve energy ; the fall in leptin reduces plasma T3 levels, and UCP1 levels in adipose tissue decline as a result of decreased SNS activity Yet, in spite of decreased SNS tone at the adipocyte, there is an obligate lipolysis due to insulin suppression and upregulation of hormone-sensitive lipase.

Lipolysis is necessary to maintain energy delivery to the musculature and brain in the form of liver-derived ketone bodies. Under conditions of fasting or caloric deprivation, vagal tone is increased. Together with the fall in T3 levels, this slows the heart rate and reduces myocardial oxygen consumption.

Heightened vagal tone also increases -cell insulin secretion and adipose insulin sensitivity; in sum, these effects promote increased energy fat storage The effects of fasting revert once caloric sufficiency is re-established and leptin levels rise. Leptin resistance prevents exogenous leptin adminis- tration from promoting weight loss The response to most weight loss regimens plateaus rapidly due to the rapid fall of peripheral leptin levels below a personal leptin threshold , which is likely genetically determined. Leptin decline causes the VMH to sense a reduction in peripheral energy stores.

This fosters a decrease in REE to conserve energy, analogous to the starvation response described earlier but occurring at elevated leptin levels. The cause of leptin resistance in obesity is likely multifactorial. First, leptin crosses the blood brain barrier via a saturable transporter, which limits the amount of leptin reaching its receptor in the VMH , Second, activation of the leptin receptor induces intraneuronal expression of suppressor of cytokine signaling-3 SOCS-3 , which limits leptin signal transduction Finally, hypertriglyceridemia limits access of peripheral leptin to the VMH and interferes with leptin signal transduction upstream of STAT-3, its primary second messenger Thus, factors that induce hypertriglyceridemia, such as dietary fructose and insulin resistance, tend to promote leptin resistance Two clinical paradigms have been shown to improve leptin sensitivity.

After weight loss through caloric restriction, exogenous administration of leptin can then increase REE back to baseline and permit further weight loss , This suggests that weight loss itself improves leptin sensitivity. Second, suppression of insulin correlates with improvement in leptin sensitivity and promotes weight loss , suggesting that hyperinsulinemia promotes leptin resistance by interfering with leptin signal transduction in the VMH and VTA Indeed, insulin reduction strategies may be effective in promoting weight loss in obese children by improving leptin sensitivity This has led to the hypothesis that chronic hyperinsulinemia functions to block leptin signal transduction at the VMH and VTA, which turns a negative feedback cycle into a vicious feedforward cycle Fig.

However, this hypothesis remains to be proven. The limbic triangle. Three areas of the CNS conspire to drive food intake and reduce physical activity, result- ing in persistent weight gain. The ventromedial hypothalamus VMH transduces the leptin signal from adipocytes to reduce energy intake and increase energy expenditure; however, hyperinsulinemia inhibits leptin signaling, promoting the starvation response.

The ventral tegmental area VTA transduces the leptin signal to reduce dopamine neuro- transmission to the nucleus accumbens NA to reduce palatable food intake; however, insulin resistance and leptin resistance increase dopamine neurotransmission and promote the reward of food.

The amygdala transduces fear and stress, resulting in increased cortisol, which also drives energy-rich food intake and promotes insulin resistance, further interfering with leptin signaling at the other two CNS sites. Thus, interference with any of the negative feed- back aspects of the limbic triangle transforms it into a positive feedback loop, promoting continued weight gain and obesity.

Penetrating analyses of the obesity epidemic in its social, cultural, economic, and political contexts highlight challenges and opportunities for obesity prevention and community action. The perspective is international in scope and reflects the expertise and experience of many of the leading figures in the field.

Comprehensive and up-to-date, this new edition of Pediatric Obesity: Etiology, Pathogenesis and Treatment will be an invaluable guide for all healthcare providers and policy makers concerned with the evaluation and care of children with nutritional and metabolic disease and with the societal implications of the obesity epidemic. Michael S. Freemark, MD, Robert C. It covers all the basic sciences, social sciences, and clinical sciences that play a role in pediatric obesity. The most unique feature of this book is that at the end of each chapter, the author submits questions to the chapter authors.

It highlights challenges and opportunities for pediatric obesity prevention and community action. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser. King; Nuala M. Byrne Routledge, Kopelman Martin Dunitz, Levin, Edward D. Slotkin, Theodore A. Walker, Vickie R. Thayer, Kristina A. Holloway, Alison C. Environmental Health Perspectives, Vol. Clinical Psychiatry News, Vol.