Obesity is a leading cause of morbidity and mortality as a risk factor for diabetes, cardiovascular disease, and cancer. The central melanocortin system is a critical circuit in the regulation of body weight and composition, with haploinsufficiency of the melanocortin-4 receptor (MC4-R) in humans the most common monogenic cause of severe obesity, accounting for up to 5% of cases. Consequently, a thorough understanding of the central melanocortin system will increase our understanding of obesity, improve differential diagnosis of obesity syndromes, and ultimately identify potential targets for drug development for the treatment of disorders of energy homeostasis. Much of the research in the field has been focused on the regulation of the arcuate proopiomelanocortin (POMC) neurons by leptin, and their role in mediating the long-term adipostatic leptin signal. Work from the first funding period of this grant also demonstrated an important role of the melanocortin system in satiety, and sensing of nutrient intake. Using an electrophysiological system developed in this laboratory for recording from arcuate POMC and NPY neurons, as well as neuroanatomical methods, we have discovered that these neurons not only respond to leptin, but are also regulated by acute hunger and satiety factors such as PYY3-36, insulin, CCK, and ghrelin. Likewise, in preliminary data provided here we show that MC4-R signaling also has an impact on gastric emptying, identifying a novel efferent pathway for regulation of satiety by this system. Indeed, data just published on MC4-R haploinsufficient humans documents a profound hyperphagia, and perhaps even binge eating in these individuals. These findings raise two intriguing hypotheses. First, most hunger and satiety signals are transmitted to the CNS via vagal afferents and humoral inputs to the brainstem. POMC is also expressed in a poorly characterized set of neurons in the nucleus of the solitary tract (NTS) in the brainstem, and the dorsal motor nucleus of the vagus, a key site of motor neurons regulating GI function, is a dense site of MC4-R expression. Thus, the central melanocortin system may be an important pathway for sensing and responding to hunger and satiety siqnals acting through vaqa! and humoral inputs to the brainstem melanocortin system, and perhaps, in the case of some humoral factors even acting directly on arcuate POMC neurons. Secondly, arcuate and brainstem POMC neurons send projections to a number of MC4-R-containing sites involved in autonomic outflow, like the PVN, DMH, IML, PBL, and DMV, and stereotaxic injection of melanocortJn compounds into the PVN can profoundly impact feeding behavior. Thus, the regulation of autonomic outflow to the gut by the melanocortin system may be an important pathway by which this system participates in the regulation of energy intake. In this next funding period, we will continue to characterize regulatory inputs to the central melanocortin system, and effector output pathways, with a focus on the role of the system in sensing and responding to acute hunger and satiety signals.
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