MC3R inhibition as a strategy to maintain weight loss in obesity

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Proposal Summary: The increasing rates of obesity and associated metabolic syndrome pose a major public health concern. Although behavioral (diet and/or exercise), surgical, and pharmacological modalities exist for weight loss, many individuals are unable to maintain this weight loss due to behavioral and neuroendocrine adaptions in the brain promoting weight re-gain. Therefore, pathways preventing compensatory adaptations to weight loss would provide a wholly novel approach to the conundrum of obesity treatment. Hypothalamic agouti-related peptide (AgRP) neurons are activated by hunger and dieting and potently engage behavioral and neuroendocrine neural circuits to drive behaviors promoting increased food intake and rebound weight gain. Here, we show that the melanocortin 3 receptor is densely expressed in AgRP neurons, with 97% of AgRP neurons containing MC3R. Furthermore, pharmacological manipulation of MC3R bi-directionally regulates feeding in an AgRP neuron dependent manner, with agonism of MC3R stimulating feeding and antagonism of MC3R suppressing feeding. Consistently, mice with impaired MC3R function do not re-feed normally following both fasting and caloric restriction and fail to adequately activate neuroendocrine responses to weight loss. In this proposal, we will evaluate the utility of MC3R specific antagonists as a therapeutic strategy for preventing compensatory responses to weight loss. We will also determine the cellular and molecular mechanism(s) mediating the anorexigenic effects of MC3R antagonism. The principle investigator in this training grant, Dr. Patrick Sweeney, has extensive experience in behavioral neuroscience and mouse feeding behavior. In this training grant, Dr. Sweeney will receive additional training in metabolic physiology, neuroendocrinology, obesity biology, and pharmacology from the primary research mentor, Dr. Roger Cone. Furthermore, under the guidance of an expert team of collaborators, Dr. Sweeney will receive hands on training in brain slice electrophysiology and in vivo endomicroscopic brain imaging. Together, the mentorship and training in this K99/R00 application will provide the necessary technical and conceptual background for Dr. Sweeney to initiate an independent research program focusing on MC3R neural circuits as therapeutic targets for obesity and eating disorders.