Project Summary According to the CDC more that 35% of U.S. adults are obese and therefore are at risk of life-threatening diseases including diabetes, stroke, heart disease and cancers. Further, obesity has huge economic consequences in medical care and lost wages. Studies on obesity clearly indicate important roles for hypothalamic peptide transmitters in regulating aspects of energy homeostasis. Recently, we have shown that in addition to peptide transmitters, hypothalamic neurons expressing the proopiomelanocortin (POMC) gene, which potently affect energy balance, also release the fast-acting amino acid transmitters GABA and glutamate. The primary goal of this proposal is to test the hypothesis that amino acid transmitters released from POMC neurons play a key role in the regulation of metabolism, not by altering food intake, but by affecting glucose regulation and energy expenditure. In testing this hypothesis, we will 1) determine where these additional transmitters act in the brain, 2) determine the resulting consequences when these transmitters are disturbed and 3) determine if the release of these transmitters is sensitive to food intake or select peptides that signal energy state. Ultimately, understanding the neural consequences and regulation of amino acid transmitter release from POMC neurons will allow for a more comprehensive view of how these neurons exert their physiologic functions and could reveal additional levels of dysfunction leading to altered metabolism and may indicate better intervention strategies for energy balance disorders.