Factors promoting and ameliorating the development of obesity.

Obesity develops when energy intake exceeds expenditure. A constant neural, metabolic and hormonal "conversation" between the brain and periphery underlies the defense of a given level of adiposity. For the majority of humans, obesity becomes a permanent condition once it develops, possibly because of irreversible changes in the distributed network of specialized "metabolic sensing" neurons which regulate energy intake, expenditure and storage. Plasma leptin and insulin are catabolic hormones whose levels reflect the amount of adiposity and act as signal to metabolic sensing neurons. Obesity-prone individuals have an inborn reduction in their catabolic responses to glucose, leptin and insulin. These raised metabolic and hormonal sensing thresholds precede the development of obesity and predispose individuals to become and remain obese on energy dense diets. High fat diets exacerbate this problem by independently inhibiting central insulin and leptin signaling. In addition, intake of highly palatable diets overrides the homeostatic controls of ingestion because it is regulated by neural systems mediating reward and motivation. The genetic predisposition to become obese is accentuated in offspring of mothers who are obese or nutritionally deprived during gestation and/or lactation or by overfeeding during the early postnatal period. On the other hand, chronic stress and illness can both reduce adiposity, as does gastric bypass surgery. However, for chronic obesity treatment, both exercise and pharmacotherapy help but both must be continued chronically to provide sustained lowering of body weight in obese subjects. Given the permanent upward resetting of body weight set-point that occurs when genetically predisposed individuals become obese, identification of factors that prevent the development of obesity is likely to be the most successful means of ameliorating the current obesity epidemic.