The etiology of obesity is complex and incompletely understood. Involved are genetic, environmental, and psychologic factors. However, simply put, obesity is a disorder of energy balance. The two sides of the energy equation, intake and expenditure, are finely regulated by neural and hormonal mechanisms, so that body weight is maintained within a narrow range for many years. Apparently, this fine balance is controlled by an internal set point, or “lipostat,” that senses the quantity of energy stores (adipose tissue) and appropriately regulates food intake as well as energy expenditure. Several “obesity genes” have been identified. As might be expected, they encode the molecular components of the physiologic system that regulates energy balance. A key player in energy homeostasis is the LEP gene and its product, leptin. This unique member of the cytokine family, secreted by adipocytes, regulates both sides of the energy equation—intake of food and expenditure of energy. As discussed later, the net effect of leptin is to reduce food intake and to enhance the expenditure of energy.
In a simplified way, the neurohumoral mechanisms that regulate energy balance and body weight may be divided into three components (
Fig. 8.23
The peripheral or afferent system generates signals from various sites. Its main components are leptin and adiponectin produced by fat cells, insulin from the pancreas, ghrelin from the stomach, and peptide YY from the ileum and colon. Leptin reduces food intake and is discussed in further detail later. Ghrelin secretion stimulates appetite, and it may function as a “meal-initiating” signal. Peptide YY, which is released postprandially by endocrine cells in the ileum and colon, is a satiety signal.
The arcuate nucleus in the hypothalamus, processes and integrates the peripheral signals and generates new signals that are transmitted by (1) POMC (proopiomelanocortin) and CART (cocaine-and amphetamine-regulated transcript) neurons; and (2) NPY (neuropeptide Y) and AgRP (agouti-related peptide) neurons.
The efferent system, which consists of hypothalamic neurons regulated by the arcuate nucleus, is organized along two pathways, anabolic and catabolic, which control food intake and energy expenditure, respectively.
POMC/CART neurons activate efferent neurons that enhance energy expenditure and weight loss through the production of molecules such as α-melanocyte stimulating hormone (MSH) that reduce food intake (anorexigenic effect). MSH signals through melanocortin receptor (MC4R). By contrast NPY/AgRP neurons activate efferent neurons that promote food intake (orexigenic effect) and weight gain. Signals transmitted by efferent neurons also communicate with forebrain and midbrain centers that control the autonomic nervous system.
Discussed next are two important components of the afferent system that regulate appetite and satiety: leptin and gut hormones, and adiponectin that regulates fat consumption.
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