We are witnessing an emerging epidemic of obesity and type 2 diabetes. The peroxisome proliferators-activated receptors (PPARs) are a family of nuclear receptors that control the expression of genes involved in cellular fatty acid metabolism. Using genetically-modified mice, we have recently unveiled exciting links between the muscle PPARalpha pathway and obesity-related insulin resistance. PPARalpha deficiency protects against insulin resistance and diabetes despite the development of an obese phenotype. Conversely, transgenic mice with muscle-specific overexpression of PPARalpha develop diet-induced glucose intolerance and insulin resistance despite maintaining a lean phenotype. This renewal proposal is designed to test the hypothesis that in states of caloric excess, re-direction of lipid to extra-adipose tissues, such as skeletal muscle, triggers PPARalpha-driven increases in mitochondrial fatty acid oxidation and reciprocal reduction in glucose utilization through gene regulatory mechanisms independent of the insulin signaling machinery. It is also proposed that over the long-term, increased fatty acid flux through oxidative pathways leads to muscle mitochondrial dysfunction. The objectives of this proposal will be achieved using genetically-modified mice and UCP-DTA mice, a murine model of Metabolic Syndrome and type 2 diabetes. Experiments proposed in Specific Aim 1 are designed to characterize the molecular regulatory mechanisms involved in the glucose intolerance and insulin resistance related to PPARalpha-driven increases in skeletal muscle fatty acid oxidation. The goal of Specific Aim 2 is to compare the effects of PPARbeta/delta and PPARalpha on gene regulation, muscle metabolism, obesity, and insulin resistance. Specific Aim 3 is designed to characterize the effects of the PPAR coactivators, PGC-1alpha and PGC-1beta, on muscle metabolism, and insulin resistance. Specific Aim 4 involves a series of intervention experiments aimed at modulating PPARalpha-driven skeletal muscle metabolic derangements. In the short-term we seek to develop a clear conceptual framework for the interaction between derangements in muscle lipid metabolism, and the development of diabetes. A long-term goal is to identify novel therapeutic targets relevant to Metabolic Syndrome.