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 to a shift to a positive energy balance through some combination of increased food/energy intake and decreased total energy expenditure. 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 metabolic regulation. One route of metabolic regulation may be the control of food/energy intake through a liver/brain axis. The main goal of the proposed 5-year research career development plan is to facilitate the applicant's transition from postdoctoral fellow to a fully independent academic scientist. This will be accomplished by training the applicant in a variety of metabolic, neurophysiology, and molecular techniques that will be used to identify mechanisms by which the hepatic mitochondrial function impacts short-term, western diet- induced weight gain. Reduced liver fatty acid oxidation and lower hepatic energy status results in increased food intake, which requires intact vagal nerve communication between the brain and the liver. Additionally, we have shown that increased food/energy intake, weight gain, and adiposity are associated with decreased hepatic fatty acid oxidation and mitochondrial respiratory capacity during a 3-day high fat diet (HFD). The central hypothesis of this proposal is that reduced hepatic mitochondrial function results in increased acute HFD-induced weight gain via: 1) increased HFD food intake, and 2) decreased hepatic and systemic utilization of fat. In this proposal, we will use a liver-specific, PGC-1α heterozygous (LPGC1a+/-) mouse model to study the role of reduced hepatic mitochondrial respiratory function on HFD-induced weight gain. Hepatic vagotomy will be used to test the involvement of liver/brain afferent signals in LPGC1a+/- and wildtype mice. Additional work will include experiments to study the role of hepatic mitochondrial function in onset of metabolic inflexibility and control of systemic substrate utilization, and the role of liver adenine nucleotide levels in the initiation of hepatic efferent vagal signal.