The incidence of obesity, insulin resistance and type 2 diabetes is increasing dramatically world wide. The hyperglycemia, observed with insulin resistance, arises in part from increased hepatic glucose production (gluconeogenesis). However in the liver of insulin resistant patients, insulin paradoxically continues to inhibit fatty acid oxidation and promote triglyceride synthesis leading to hepatic steatosis. Many of these metabolic derangements arise in part from changes in gene expression. Our studies will investigate the regulation of key genes in the pathways of fatty acid oxidation and pyruvate metabolism by the peroxisome proliferator activated receptor gamma coactivator (PGC-1?). PGC-1??stimulates the expression of genes involved in fatty acid oxidation and hepatic gluconeogenesis while reducing glucose oxidation. PGC-1??regulates gene expression in part through interactions with nuclear receptors, and PGC-1??levels are elevated in the livers of insulin resistant animals. The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA. The phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK) inactivates PDC. PDC is a highly regulated enzymatic step in the oxidation of glucose and pyruvate to acetyl-CoA. We have found that PGC-1??in conjunction with the estrogen related receptor (ERR?) induces the PDK4 gene in hepatocytes. ERR??is an orphan nuclear receptor that induces fatty acid oxidation in muscle. We will investigate the mechanisms by which insulin inhibits the induction of PDK4 by PGC-1??and ERR?. We will examine several aspects of the PGC-1??mediated induction of hepatic fatty acid oxidation. First, we will investigate the direct induction of the carnitine palmitoyltransferase (CPT) system by PGC-1??and ERR?. The CPT system controls the entry of long chain fatty acids into mitochondria for ?-oxidation. CPT-I, which is the initiating enzyme in fatty acid translocation into mitochondria, is inhibited by malonyl-CoA. We found that PGC-1??stimulates malonyl-CoA decarboxylase (MCD). It will be determined if the elevation of MCD by PGC-1??contributes to increased hepatic mitochondrial fatty acid oxidation. Very long chain fatty acids and fish oils are oxidized in peroxisomes. We have identified several peroxisomal genes that are induced by PGC-1??and will examine the novel role of PGC-1??in stimulating the peroxisomal oxidation of very long chain fatty acids. Overall, these studies will provide new insights into the regulation of genes controlling glucose and lipid oxidation by PGC-1?.
Disorders in the metabolism of fatty aicds, glucose and pyruvate contribute to the complications of obesity and insulin resistance. Our studies will define mechanisms by which PGC-1 controls metabolism and will add to our understanding of therapies directed towards the reduction of hepatic insulin resistance. Enhancing fatty acid oxidation by activating PGC-1??could have a beneficial clinical impact by reducing hepatic steatosis which is directly associated with elevated insulin resistance and decreased mitochondrial function.
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