PROJECT 2 (MORRIS): PROJECT SUMMARY Obesity is the strongest independent predictor for the onset and progression of metabolic diseases, such as type 2 diabetes and cardiovascular disease. Weight gain occurs due combination of increased food/energy intake and decreased total energy expenditure to create a positive energy balance. Energy balance is not constant or consistent, and therefore long-term weight gain occurs as a sum of numerous, small positive fluctuations over time scales ranging from days to seasons. These acute episodes of positive energy balance occur as a complex interaction of the current obesogenic environment and inappropriate regulation of energy homeostasis. Energy homeostasis is regulated through the integration of peripheral neural, hormonal and nutrient signals by a complex, interconnected central network, including the ventromedial nucleus of the hypothalamus (VMH). The VMH has been observed as involved in the regulation of both components of energy balance, energy expenditure and energy intake, making it an important component of body weight regulation. The main goal of the proposed 3-year research plan is to establish an independent research line investigating the role of mitochondrial lipid metabolism in ventromedial hypothalamus neurons on the regulation of energy homeostasis. Activation of pathways involved in sensing reduced cellular energy state in the VMH have been proposed to increase food intake through acute activation of neuron lipid metabolism. Further, inhibition of these same pathways has been observed to increase whole-body energy expenditure. However, it is unknown whether regulation of these two components of energy homeostasis is dependent upon mitochondrial lipid metabolism in VMH neurons. The central hypothesis of this proposal is that neuronal mitochondrial lipid metabolism in the VMH modulates systemic energy homeostasis regulation during exposure to energy dense diets through control of 1) food intake and 2) energy expenditure. In this proposal, we will use a VMH-specific, PGC-1α knockout (VPGC1a- /-) mouse model to study the role of neuron mitochondrial fatty acid oxidation and respiratory function on food intake regulation during fasting and satiety hormone exposure. Additional studies will examine whether modulation of neuronal mitochondria lipid metabolism impacts high-fat/high-sucrose-induced weight gain. As a corollary, both sets of studies will utilize adeno-associated virus to increase mitochondrial lipid metabolism in VMH neurons through overexpression of PGC1a.