PHYSICAL EXAMINATION

LABORATORY STUDIES

DIAGNOSIS

Obesity

PATHOPHYSIOLOGY OF KEY SYMPTOMS

The patient’s symptoms are tied to an imbalance between caloric intake and metabolic expenditure. An increase in body weight reduces physical stamina, and a reduced physical stamina often diminishes the quantity of calories expended by exercise. Changes in lifestyle often disrupt both eating patterns and activity patterns and can lead to changes in body weight. Eating patterns are regulated by complex interaction of physiologic factors such as hunger, environmental factors, and cultural factors.

At the level of physiology, food intake is regulated predominantly by the hunger and satiety centers of the hypothalamus. The hunger center is tonically active and contributes to appetite. After a sufficient quantity and quality of food is ingested, the hypothalamic satiety center is activated, which inhibits the hunger center. There are two major theories regarding activation of the satiety center, one suggesting that glucose utilization is the appropriate activator and a second suggesting that the body fat stores provide a signal that regulates the satiety center.

Within the hypothalamus, the pro-opiomelanocortin (POMC) neurons secrete alpha-melanocyte–stimulating hormone and the cocaine- and amphetamine-related transcript (CART), both of which decrease food intake and increase energy expenditure. Insulin, leptin, and cholecystokinin (CCK) activate the POMC neurons (Fig. 67-1). Increased food intake is mediated by the neurons that produce neuropeptide Y (NPY) and the agouti-related protein (AGRP). Ghrelin activates the AGRP/NPY neurons, stimulating hunger. There are overriding neurotransmitters and hormones that influence the feeding and satiety centers (Table 67-1).

FIGURE 67–1 Control of energy balance by two types of neurons of the arcuate nuclei: (1) pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte–stimulating hormone (α-MSH) and cocaine- and amphetamine-regulated transcript (CART), decreasing food intake and increasing energy expenditure; and (2) neurons that produce agouti-related protein (AGRP) and neuropeptide Y (NPY), increasing food intake and reducing energy expenditure. α-MSH released by POMC neurons stimulates melanocortin receptors (MCR-3 and MCR-4) in the paraventricular nuclei (PVN), which then activate neuronal pathways that project to the nucleus tractus solitarius (NTS) and increase sympathetic activity and energy expenditure. AGRP acts as an antagonist of MCR-4. Insulin, leptin, and cholecystokinin (CCK) are hormones that inhibit AGRP-NPY neurons and stimulate adjacent POMC-CART neurons, thereby reducing food intake. Ghrelin, a hormone secreted from the stomach, activates AGRP-NPY neurons and stimulates food intake. LepR, leptin receptor; Y₁R₁, neuropeptide Y₁ receptor.

(Redrawn from Barsh GS, Schwartz MW: Nat Rev Genet 3:589, 2002).