Interactions of Leptin and the Melanocortin System

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PROJECT SUMMARY The increasing rates of obesity and diabetes highlight the need to understand the brain circuits and cellular mechanisms regulating energy balance and glucose homeostasis. Prominent among these is the central leptin- melanocortin system, which includes the pro-opiomelanocortin (POMC) neurons, subsets of which express leptin receptors (LEPRs). While enormous strides have been made to understand the role of hypothalamic POMC neurons that produce α-MSH in metabolism, relatively little is known about how the three isoforms of - MSH produced in hypothalamus and pituitary gland POMC-expressing cells respond to metabolic challenges. The current application extends our previous discovery that LEPR-expressing POMC neurons are required for coordinating hepatic glucose production and responding to metabolic challenges. We will determine the roles for -MSH peptides produced from POMC neurons in the regulation of metabolism in dynamic challenges. This project is also significant because it will be the first to combine the power of mouse genetics with advanced mass spectrometry to quantitatively measure and map specific POMC-derived -MSH peptides in hypothalamic and pituitary tissues. We will also correlate -MSH peptide levels with parameters of energy and glucose homeostasis, and deermine which peptides underlie metabolic adaptation. These studies will broaden our understanding of the functional mechanism by which the leptin-melanocortin system regulates endocrine and autonomic functions, particularly at the level of liver and adipose tissues.