Peptide signals regulating food intake and energy homeostasis

The adiposity hormone leptin has been shown to decrease food intake and body weight by acting on neuropeptide circuits in the hypothalamus. However, it is not clear how this primary hypothalamic action of leptin is translated into a change in food intake. We hypothesize that the behavioral effect of leptin ultimately involves the integration of neuronal responses in the forebrain with those in the nucleus tractus solitarius in the caudal brainstem, where ingestive behavior signals are received from the gastrointestinal system and the blood. One example is the peptide cholecystokinin, which is released from the gut following ingestion of a meal and acts via vagal afferent nerve fibers to activate medial nucleus tractus solitarius neurons and thereby decrease meal size. While it is established that leptin acts in the arcuate nucleus in the hypothalamus to stimulate anorexigenic neurons that inhibit food intake while simulataneously inhibiting orexigenic neurons that increase food intake, the mechanisms linking these effects with regions of the caudal brainstem that integrate cues related to meal termination are unclear. Based on an increasing body of supportive data, we hypothesize that this integration involves a pathway comprising descending projections from neurons from the paraventricular nucleus to neurons within the nucleus tractus solitarius that are activated by meal-related satiety factors. Leptin's anorexic effect comprises primarily decreased meal size, and at subthreshold doses for eliciting an effect on food intake, leptin intensifies the satiety response to circulating cholecystokinin. The location of neurons subserving the effects of intracerebroventricular administration of leptin and intraperitoneal injection of cholecystokinin on food intake has been identified by analysis of Fos expression. These studies reveal a distribution that includes the paraventricular nucleus and regions within the caudal brainstem, with the medial nucleus tractus solitarius having the most pronounced Fos expression in response to leptin and cholecystokinin, and support the hypothesis that the long-term adiposity signal leptin and the short-term satiety signal cholecystokinin act in concert to maintain body weight homeostasis.