The mechanisms through which insulin and an insulin-mimetic regulate food intake and body weight

Insulin has long been recognized to play an important role in the regulation of energy balance. It is secreted from the pancreas in direct proportion to adipose stores and acts in the hypothalamus to decrease food intake and body weight. However, little progress has been made in elucidating the brain systems through which insulin exerts these effects. The studies presented here identify the melanocortin system as a key mediator of insulin's actions in the brain. First, insulin receptors were localized to pro-opiomelanocortin (POMC) neurons. Second, i.c.v. administration of insulin stimulated POMC expression in the hypothalamus. Third, antagonism of melanocortin receptors blocked insulin-induced hypophagia. Leptin, a hormone that also reduces body weight, has previously been found to act through the melanocortin system. Therefore, the interaction between leptin and insulin was also characterized and found to be sub-additive, indicating redundancy between these two hormones.; Although insulin promotes weight loss through its actions in the central nervous system (CNS), increased insulin signaling in the periphery is associated with weight gain. Therefore the ability of a small, lipophilic, non-peptidyl, insulin-mimetic compound (L-783,281) to regulate energy balance was assessed. The data presented here illustrate that L-783,281 acts in the CNS to reduce food intake and body weight and increase energy expenditure. These effects were independent of visceral illness. In addition, L-783,281 was found to increase POMC expression and decrease the expression of the orexigenic compound, Neuropeptide Y. These studies, in concert with the fact that an analog of L-783,281 prevents diet-induced obesity when administered orally, suggest that the insulin system may be an appropriate target for the treatment of obesity.