Mammalian liver has evolved as a key organ in the maintenance of systemic glucose and lipid homeostasis. Hepatic glucose secretion is essential for maintaining nearly constant glucose levels under various nutritional conditions. The transcriptional coactivator PGC-1alpha has been shown to activate the entire program of gluconeogenesis; elevated PGC-1alpha activities may be a major contributor to hyperglycemia in diabetes. In addition, PGC-1alpha induces the expression of genes involved in a-oxidation of fatty acids and ketogenesis, suggesting that PGC-1alpha may underlie the broad program of metabolic adaptation to fasting in the liver. Recently we have shown that PGC-1beta, a coactivator closely related to PGC-1alpha, drastically elevates plasma triglyceride levels when expressed in the rat liver. These findings raise the possibility that PGC-1beta may be a key factor in the control of lipid homeostasis and play an important role in the pathogenesis of dyslipidemia in obesity and diabetes. This proposal describes several experiments to critically assess the role of PGC-1a in hepatic gluconeogenesis in response to fasting and in diabetes. These studies will also provide insight in to the control of multiple metabolic programs in the liver that enable an organism to survive in the face of nutritional deprivation. Using mouse genetic approaches, the function of PGC-1beta in the control of lipid metabolism will be examined, and importantly, its involvement in the pathogenesis of dyslipidemia will be investigated. The mechanistic basis of PGC-1beta action will be explored. Finally, a crucial aspect of the metabolic regulation by the PGC-1 family coactivators is to establish how their activities are modulated. The proposed studies will not only enhance our knowledge about the control of cellular energy metabolism, but also reveal novel therapeutic targets for the treatment of diabetes and its associated complications.
