Whole body glucose metabolism is governed by both peripheral and central (brain) mechanisms. The ventromedial nucleus of the hypothalamus (VMH) in the brain plays an important role in glucose sensing and hypoglycemia-related adaptations of the autonomic nervous system. However, how intracellular signaling modalities within VMH neurons bring about physiological and pathological responses to the changing glucose environment remains elusive. Our preliminary data revealed a temporal relationship between VMH neuronal mitochondrial dynamics and phenotypic characteristics of glucose fluctuation-induced responses in mice. Our preliminary results suggest that mitochondrial proteins, including uncoupling protein 2 (UCP2) and Dynamin- related peptide 1 (DRP1) are involved in cellular adaptions of VMH neurons to glucose level alterations, and, that interference with these proteins in a VMH-specific manner affect whole body glucose metabolism. Because both of these proteins promoted mitochondrial fission in VMH neurons, we hypothesize that mitochondrial dynamics, with particular emphasis on mitochondrial fission, are crucial cellular biological processes in the VMH to control of whole body glucose metabolism. In this proposal, we aim to decipher mechanistic aspects of VMH mitochondrial dynamics in glucose control. Specifically, we hypothesize that UCP2 and DRP1 are important components in the central regulation of glucose metabolism. Their interaction is crucial to properly adjust VMH neuronal responses to shifts in glucose levels. We also predict that impaired glucose metabolism in diabetic mice is the consequence of increased fusion in VMH neurons. To test these hypotheses, we propose 3 Aims: Aim 1 will test the hypothesis that UCP2 is sufficient and necessary in the VMH to regulate glucose metabolism. Aim 2 will test the hypothesis that glucose-induced increased UCP2 induces mitochondrial fission mediated by DRP1 and this mechanism is critical in the central regulation of glucose metabolism. Aim 3 will test the hypothesis that impaired glucose metabolism in diabetic mice is the consequence of increased mitochondrial fusion in VMH neurons and that interference with this mitochondrial mechanism in VMH neurons will improve whole body glucose metabolism in diabetic mice. The execution of these studies will deliver novel insights into central regulation of whole body glucose metabolism and offer novel avenues to combat diabetes by targeting brain mitochondrial dynamics.