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triggered by a meal circulate to adipose tissue and induce adipocyte leptin secretion. Leptin circulates to the hypothalamus, where

it binds receptors in the arcuate nucleus to induce satiety, leading to decreased food intake. Leptin is one of many signals that

mediates bidirectional communication between gut, adipose tissue, and brain. Other organ systems are also involved, including

immune and reproductive systems and the liver. B: Leptin regulates allostatic control of short-term and long-term food intake.

Postprandial leptin secretion induces satiety for a period of hours, after which leptin levels and satiety wane, prompting food

intake. Similarly, leptin, along with other mediators of food intake, controls long-term weight regulation: diet-induced weight loss

leads to decreased adipose tissue mass, reducing peak postprandial leptin levels, leading to decreased postprandial satiety and

increased food intake at each subsequent meal until adipose tissue mass is restored to set-point levels. In this manner, leptin

functions as a component of the adipostat. This allostatic control provides an explanation for rebound weight gain after dietinduced weight loss.

The control of feeding behavior and nutrient intake is a highly regulated process centered in the

hypothalamus, which integrates information regarding nutritional status, environment, and energy

expenditure via central and peripheral orexigenic and anorexigenic signals. Peripheral messengers

include signals from adipose tissue (adipokines), including leptin and adiponectin, cytokines, such as TNFα and interleukin (IL-6), and gut peptides. Among this diverse latter class of mediators, ghrelin is a

dominant stimulant of feeding. Ghrelin is expressed primarily by oxyntic glands in the fundus of the

stomach. Gastric ghrelin–producing cells represent about one-fourth of endocrine cells within the gastric

mucosa. Ghrelin is also produced in the hypothalamus.

Encoded by five exons, preproghrelin undergoes endoproteolytic processing and posttranslational

modification to yield des-acyl ghrelin and acyl ghrelin. Both hormones share the same amino acid

sequence, and both are detectable in blood, but acyl ghrelin, which undergoes acylation of the Ser3

residue, is the active form. Acyl ghrelin regulates feeding, metabolic activity, and insulin secretion. The

enzyme-mediating acylation is the membrane-bound ghrelin O-acyltransferase (GOAT). Genetic

disruption of the GOAT gene in mice leads to complete absence of acyl ghrelin. GOAT inhibition

improves glucose tolerance and reduces weight gain in mice. Plasma acyl-ghrelin levels increase with

fasting and decrease after feeding, a pattern indicating that ghrelin is involved in meal initiation. The

ghrelin receptor is a member of the family of G protein–coupled receptors and contains seven

transmembrane domains. Ghrelin receptors are widely distributed among both central and peripheral

tissues, including the pituitary gland, hypothalamus, pancreas, stomach, and intestine. Ghrelin causes

growth hormone secretion following peripheral or central administration, and release of growth

hormone from cultured pituitary cells.

Ghrelin is the only orexigenic hormone identified to date. The relative scarcity of orexigenic proteins

relative to anorexigenic proteins underscores an important fundamental characteristic of the global

regulation of food intake, which is biased toward chronic basal hunger regulated by multiple satiety

factors (rather than chronic basal satiety regulated by multiple hunger factors). This central feature of

food intake control systems predisposes to excess food intake and thus provides a selective advantage in

environments of food scarcity during our evolution, but leads to obesity in our modern environment. In

humans, the intravenous administration of ghrelin at physiologic concentrations induces the sensation of

hunger and stimulates oral intake. Circulating ghrelin levels peak just prior to meal initiation and

decline rapidly postprandially. Ghrelin secretion is increased by weight loss and by restriction of caloric

intake. Serum ghrelin levels are increased in anorexic individuals and depressed in obese subjects. In

animals, ghrelin administration has been found to stimulate food intake, to induce growth of adipose

tissues, and to increase body weight. The administration of ghrelin antibody or ghrelin receptor

antagonists blunts ghrelin-induced weight gain and positive energy balance. Similar molecules are under

active study as potential therapeutic agents.

Ghrelin is a circulating hormone with CNS effects. The arcuate nucleus of the hypothalamus is a

crucial site for the integration of fasting and feeding signals. Two types of neurons, with opposing

actions on feeding behavior, have been identified in the arcuate nucleus. Neurons that express

proopiomelanocortin and cocaine- and amphetamine-regulated transcript (CART) suppress food intake,

reduce body weight, and increase energy expenditure. In contrast, neurons producing neuropeptide Y

and agouti gene–related transcript (AgRP) are orexigenic. These cells act to stimulate food intake and

reduce energy expenditure. Ghrelin, as well as leptin and multiple other gut peptides, adipokines, and

cytokines, directly mediate the activities of these two types of neurons (Fig. 4-3). Direct peripheral

effects of ghrelin on peripheral tissues also contribute to the regulation of body weight and energy

homeostasis.

Leptin and ghrelin are paradigmatic adipokine and gut peptide mediators of food intake respectively,

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but multiple other proteins contribute. Adipokines that regulate satiety include adiponectin, visfatin,

apelin, and lipocalin; gut peptides include glucose-dependent insulinotropic peptide (GIP), glucagon-like

peptide-1 (GLP-1), nesfatin-1, oxyntomodulin, pancreatic polypeptide, cholecystokinin, amylin,

glucagon, somatostatin, cholecystokinin, and insulin. Finally, cytokines, including TNF-α and IL-6, in

addition to immunoregulatory functions, also play important roles in the control of food intake. TNF-α,

for example, mediates anorexigenic responses in the context of cachexia and inflammatory states.

Virtually all adipokines, gut hormones, and cytokines have multiple overlapping functions that include

regulation of satiety and hunger, immune function, glucose homeostasis, lipid metabolism, and

endocrine and reproductive function (Fig. 4-4). This functional diversity speaks to the intimate

association of energy homeostasis with all aspects of physiology.

Genetic polymorphisms in the melanocortin 4 receptor gene, which regulates satiety and hunger

responses and the HFC set-point, are implicated in 5% of cases of human obesity. Similar

polymorphisms associated with obesity exist with the genes encoding leptin and its receptor, ghrelin,

neuropeptide Y, adiponectin, GLP-1, and other genes associated with the control of satiety and hunger.

These observations demonstrate that variability in the genes that regulate food intake, with

corresponding variability in the functional control of satiety and hunger, contribute to the development

of human obesity.

Metabolic rate: While less important than control of food intake, variability in metabolic rate

contributes to the pathogenesis of obesity. In obese subjects who lose weight with diet, total energy

expenditure is decreased up to 20% beyond that expected by loss of fat and fat-free mass alone, and is

accompanied by a corresponding decrease in voluntary physical activity.10 In contrast to diet-induced

weight loss, bariatric surgery-induced weight loss paradoxically induces increased energy expenditure,

which may explain the efficacy of surgery. In the absence of surgery however, compensatory decreases

in energy expenditure counteract caloric restriction and contribute to adipostat responses that resist

declines in adipose tissue mass. Studies of overfeeding and weight gain in obese subjects demonstrate

converse changes with a compensatory increase in total energy expenditure. Importantly, overfeeding

studies in twin cohorts demonstrate a significant genetic component to variability in energy expenditure

responses to overfeeding, suggesting that variability in metabolic rate responses to weight loss

contributes to the development of obesity in those at risk.3

Differences in sympathetic nervous system activity are observed in humans and represent a potential

mechanism underlying variability in metabolic rate. Obese humans demonstrate decreased sympathetic

nervous system activity compared to lean humans, and higher levels of sympathetic nervous system

activity predict successful diet-induced weight loss. Differences in endocrine responses also contribute,

with obese humans manifesting differences in thyroid hormone and catecholamine balance associated

with decreased metabolic rates. At the cellular level, differences in energy utilization and thermogenesis

play an important role. Skeletal muscle energy utilization efficiency is increased in humans who achieve

successful weight loss and decreased in those who gain weight. Furthermore, decreased levels of

skeletal muscle nonexercise-induced thermogenesis and diet-induced thermogenesis have been

demonstrated in obese humans.11 These observations suggest that fundamental differences in cellular

energy homeostasis contribute to obesity. The mechanisms underlying these variable cellular responses

are not fully defined, but differences in uncoupling protein (UCP) function are implicated. UCPs

uncouple oxidative phosphorylation from electron transport in mitochondria, creating a proton leak that

generates heat rather than ATP. The role of UCPs in the pathogenesis of obesity is an important area of

active research. UCP function is highly variable and genetically determined in mice, and polymorphisms

in UCP genes correlate with obesity and metabolic disease in humans, supporting a role for genetic

variability in UCP function in obesity pathogenesis. Transgenic mice overexpressing UCP-1 under

control of the adipose tissue-specific AP2 promoter are resistant to obesity, suggesting the potential

therapy for obesity based on manipulation of cellular thermogenesis and metabolic rate.

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