Modified Project Summary/Abstract Section The liver is central to mammalian metabolism and plays a critical role in providing fuel to other tissues particularly when food is limiting. People with disparate inborn errors in mitochondrial fatty acid β-oxidation exhibit life-threatening hypoketotic-hypoglycemia following a fast due to the critical role of fatty acid oxidation to gluconeogenesis and ketogenesis. To understand the contribution of hepatic fatty acid oxidation to systemic metabolic dysfunction, we have generated multiple transgenic mice with an altered ability to oxidize long chain fatty acids via mitochondrial β-oxidation specifically in hepatocytes. Here we will leverage extensive genetic models to understand the contribution of fatty acid oxidation to hepatic and extrahepatic regulation of hepatic and systemic metabolic homeostasis. The expectation is that our proposed studies will describe novel requirements and signaling roles of hepatic fatty acid oxidation that impact the development of obesity and glucose intolerance.