Molecular Influences of Obesity

The cause of obesity can be summarized in a deceptively simple application of the first law of thermodynamics: Obesity results when energy (caloric) intake exceeds energy expenditure. However, the mechanism underlying this imbalance involves a complex interaction of biochemical, neurologic, environmental, and psychologic factors. The basic neural and humoral pathways that regulate appetite, energy expenditure, and body weight involve systems that regulate short-term food intake (meal to meal), and signals for the long-term (day to day, week to week, year to year) regulation of body weight (Fig. 1).

Figure 1:  Some signals that influence appetite and satiety in undernourished (A) and overnourished (B) states. CCK = cholecystokinin; PYY = peptide YY.
A. Long-term signals
Long-term signals reflect the status of fat (TAG) stores.
1. Leptin: Leptin is an adipocyte peptide hormone that is made and secreted in proportion to the size of fat stores. It acts on the brain to regulate food intake and energy expenditure. When we consume more calories than we need, body fat increases, and leptin production by adipocytes increases. The body adapts by increasing energy use (increasing activity) and decreasing appetite (an anorexigenic effect). When body fat decreases, the opposite effects occur. Unfortunately, most obese individuals are leptin resistant, and the leptin system may be better at preventing weight loss than preventing weight gain. [Note: Leptin’s effects are mediated through binding to receptors in the arcuate nucleus of the hypothalamus.]
2. Insulin: Obese individuals are also hyperinsulinemic. Like leptin, insulin acts on hypothalamic neurons to dampen appetite.  [Note: Obesity is associated with insulin resistance .]
B. Short-term signals
Short-term signals from the gastrointestinal (GI) tract control hunger and satiety, which affect the size and number of meals over a time course of minutes to hours. In the absence of food intake (between meals), the stomach produces ghrelin, an orexigenic (appetite-stimulating) hormone that drives hunger. As food is consumed, GI hormones, including cholecystokinin and peptide YY, among others, induce satiety (an anorexigenic effect), thereby terminating eating, through actions on gastric emptying and neural signals to the hypothalamus. Within the hypothalamus, neuropeptides (such as orexigenic neuropeptide Y [NPY] and anorexigenic α-melanocyte–stimulating hormone [α-MSH]) and neurotransmitters (such as anorexigenic serotonin and dopamine) are important in regulating hunger and satiety. Long-term and short-term signals interact, insofar as leptin increases secretion of α-MSH and decreases secretion of NPY. Thus, there are many complex regulatory loops that control the size and number of meals in relationship to the status of body fat stores. [Note: α-MSH, a cleavage product of proopiomelanocortin, binds to the melanocortin-4 receptor (MC4R). Loss-of-function mutations to MC4R are associated with early-onset obesity.]

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