Chapter 074. Biology of Obesity (Part 2)

Prevalence Data from the National Health and Nutrition Examination Surveys (NHANES) show that the percent of the American adult population with obesity (BMI 30) has increased from 14.5% (between 1976 and 1980) to 30.5% (between 1999 and 2000). As many as 64% of U.S. adults ≥20 years of age were overweight (defined as BMI 25) between the years of 1999 and 2000. Extreme obesity (BMI ≥40) has also increased and affects 4.7% of the population. The increasing prevalence of medically significant obesity raises great concern. Obesity is more common among women and in the poor; the prevalence...
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Chapter 074. Biology of Obesity (Part 2) Chapter 074. Biology of Obesity (Part 2) Prevalence Data from the National Health and Nutrition Examination Surveys(NHANES) show that the percent of the American adult population with obesity(BMI > 30) has increased from 14.5% (between 1976 and 1980) to 30.5%(between 1999 and 2000). As many as 64% of U.S. adults ≥20 years of age wereoverweight (defined as BMI > 25) between the years of 1999 and 2000. Extremeobesity (BMI ≥40) has also increased and affects 4.7% of the population. Theincreasing prevalence of medically significant obesity raises great concern.Obesity is more common among women and in the poor; the prevalence inchildren is also rising at a worrisome rate. Physiologic Regulation of Energy Balance Substantial evidence suggests that body weight is regulated by bothendocrine and neural components that ultimately influence the effector arms ofenergy intake and expenditure. This complex regulatory system is necessarybecause even small imbalances between energy intake and expenditure willultimately have large effects on body weight. For example, a 0.3% positiveimbalance over 30 years would result in a 9-kg (20-lb) weight gain. This exquisiteregulation of energy balance cannot be monitored easily by calorie-counting inrelation to physical activity. Rather, body weight regulation or dysregulationdepends on a complex interplay of hormonal and neural signals. Alterations instable weight by forced overfeeding or food deprivation induce physiologicchanges that resist these perturbations: with weight loss, appetite increases andenergy expenditure falls; with overfeeding, appetite falls and energy expenditureincreases. This latter compensatory mechanism frequently fails, however,permitting obesity to develop when food is abundant and physical activity islimited. A major regulator of these adaptive responses is the adipocyte-derivedhormone leptin, which acts through brain circuits (predominantly in thehypothalamus) to influence appetite, energy expenditure, and neuroendocrinefunction (see below). Appetite is influenced by many factors that are integrated by the brain, mostimportantly within the hypothalamus (Fig. 74-2). Signals that impinge on thehypothalamic center include neural afferents, hormones, and metabolites. Vagalinputs are particularly important, bringing information from viscera, such as gutdistention. Hormonal signals include leptin, insulin, cortisol, and gut peptides.Among the latter are ghrelin, which is made in the stomach and stimulatesfeeding, and peptide YY (PYY) and cholecystokinin, which are made in the smallintestine and signal to the brain through direct action on hypothalamic controlcenters and/or via the vagus nerve. Metabolites, including glucose, can influenceappetite, as seen by the effect of hypoglycemia to induce hunger; however,glucose is not normally a major regulator of appetite. These diverse hormonal,metabolic, and neural signals act by influencing the expression and release ofvarious hypothalamic peptides [e.g., neuropeptide Y (NPY), Agouti-relatedpeptide (AgRP), α-melanocyte-stimulating hormone (α-MSH), and melanin-concentrating hormone (MCH)] that are integrated with serotonergic,catecholaminergic, endocannabinoid, and opioid signaling pathways (see below).Psychological and cultural factors also play a role in the final expression ofappetite. Apart from rare genetic syndromes involving leptin, its receptor, and themelanocortin system, specific defects in this complex appetite control networkthat influence common cases of obesity are not well defined. Figure 74-2 The factors that regulate appetite through effects on central neuralcircuits. Some factors that increase or decrease appetite are listed. NPY,neuropeptide Y; MCH, melanin-concentrating hormone; AgRP, Agouti-relatedpeptide; MSH, melanocyte-stimulating hormone; CART, cocaine- andamphetamine-related transcript; GLP-1, glucagon-related peptide-1; CCK,cholecystokinin. Energy expenditure includes the following components: (1) resting or basalmetabolic rate; (2) the energy cost of metabolizing and storing food; (3) thethermic effect of exercise; and (4) adaptive thermogenesis, which varies inresponse to chronic caloric intake (rising with increased intake). Basal metabolicrate accounts for ~70% of daily energy expenditure, whereas active physicalactivity contributes 5–10%. Thus, a significant component of daily energyconsumption is fixed. Genetic models in mice indicate that mutations in certain genes (e.g.,targeted deletion of the insulin receptor in adipose tissue) protect against obesity,apparently by increasing energy expenditure. Adaptive thermogenesis occurs inbrown adipose tissue (BAT), which plays an important role in energy metabolismin many mammals. In contrast to white adipose tissue, which is used to storeenergy in the form of lipids, BAT expends stored energy as heat. A mitochondrialuncoupling protein (UCP-1) in BAT dissipates the hydrogen ion gradient in theoxidative respiration chain and releases energy as heat. The metabolic activity ofBAT is increased by a central action of leptin, acting through the sympatheticnervous system, which heavily innervates this tissue. In rodents, BAT deficiencycauses obesity and diabetes; stimulation of BAT with a specific adrenergic agonist(β3 agonist) protects against diabetes and obesity. Although BAT exists in humans(especially neonates), its physiologic role is not yet established. Homologues ofUCP-1 (UCP-2 and -3) may mediate uncoupled mitochondrial respiration in othertissues.