Type 2 diabetes is the most prevalent metabolic disorder in Western and developing countries, rapidly becoming a worldwide epidemic. Although the exact primary cause(s) of type 2 diabetes are not yet defined, it is clear that insulin resistance, i.e. the inability of insulin to promote glucose disposal, plays a major role in the development of the disease. Decreased mitochondrial oxidative function and an ensuing increased intracellular lipid accumulation have been proposed as underlying causes for insulin resistance. Notably, muscle in individuals with insulin resistance or type 2 diabetes has decreased expression of genes encoding mitochondrial proteins, lower content of mitochondria and mitochondrial enzymes, and reduced mitochondrial oxidative phosphorylation capacity. Recent studies have elucidated specific transcriptional networks that control mitochondrial function. The extent to which perturbations in these networks contribute to insulin resistance and the development of diabetes is currently not clear. The proposed work will test the hypothesis that the orphan nuclear receptor Estrogen Related Receptor alpha (ERRa) is a critical transcription factor regulating mitochondrial oxidative capacity and insulin sensitivity in skeletal muscle in vivo. In support of the hypothesis, ERRa is activated by signals and pathways that stimulate mitochondrial biogenesis and function in muscle, ERRa regulates mitochondrial biogenesis and function in cultured cells, and mice lacking ERRa (ERRa KO) have decreased expression of genes encoding mitochondrial proteins. To test our hypothesis we will 1) compare mitochondrial biogenesis and function in muscle of wild-type and ERRa KO mice to determine the role of ERRa in mitochondrial function in skeletal muscle; and 2) assess the effect of ERRa on insulin sensitivity in wild-type and ERRa KO mice, and in primary muscle cell cultures having or lacking ERRa. We expect to demonstrate that ERRa regulates muscle mitochondrial metabolism and plays an important role in the development of the insulin resistance that precedes type 2 diabetes. These studies will enable development of therapeutic strategies aiming at restoring mitochondrial function, ameliorating insulin resistance and preventing diabetes-associated pathologies. Relevance to public health. Diabetes is a major health problem worldwide, reaching epidemic proportions. Insulin resistance plays a major role in the development of type 2 diabetes, i.e. the most prevalent form of the disease. The proposed work uses animal models to determine the extent to which the transcriptional regulator ERRa controls mitochondrial function and determines insulin sensitivity in vivo. Establishment of an animal model with decreased mitochondrial function and susceptibility to insulin resistance will be useful for evaluating strategies that improve insulin sensitivity and decrease the incidence of diabetes. [unreadable] [unreadable] [unreadable]