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.
Obesity affects more than 35% of Americans and leads to life-threatening diseases including diabetes, stroke, heart disease and cancers. Given the high economic, societal, physical and emotional impacts of disturbed energy balance regulation it is critical to fully understand the normal and aberrant mechanisms underlying energy balance and metabolism. Stemming from the known roles for hypothalamic POMC neurons in regulating aspects of food intake and energy expenditure the proposed work will determine how the unexplored amino acid transmitters released from hypothalamic POMC neurons add to the regulation exerted by these neurons, thus increasing our understanding of an important system and potentially identifying new targets for manipulating energy balance.
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