Evidence is emerging that lipid metabolic derangements play a significant role in the development of insulin resistance and diabetes mellitus. Specifically, high levels of circulating fatty acids impinge upon the capacity of skeletal muscle to import and utilize glucose. Recent work suggests that the nuclear receptor transcription factor, peroxisome proliferator-activated receptor a (PPARa), is activated in the diabetic heart leading to counter-regulation of glucose transport and utilization, including diminished cardiac expression of the gene encoding the insulin-regulated transporter, GLUT4. However, whether similar metabolic counter-regulation occurs in non-cardiac muscle has not yet been evaluated. Moreover, the mechanisms involved in this metabolic regulatory response are unknown. We hypothesize that activation of the skeletal muscle PPARa gene regulatory pathway, such as occurs in the diabetic state, and its downstream effects on fatty acid utilization and energy production lead to specific alterations in GLUT4 gene transcription and consequently, diminished glucose uptake in skeletal muscle. This alteration in GLUT4 gene expression could be involved in the development of insulin resistance known to occur in the context of hyperlipidemic states given that PPARa is activated by fatty acids. This proposal is designed to [1] delineate the PPARa-responsive region(s) of the GLUT4 promoter, [2] identify and characterize the trans-acting factors and upstream signaling events involved in the PPARa-mediated transcriptional repression of the GLUT4 gene, and [3] characterize the metabolic phenotype of transgenic mice with skeletal muscle-specific overexpression of PPARa (MLC-PPAR mice). Accordingly, these studies will serve to dissect the molecular regulatory mechanisms involved in the down-regulation of GLUT4 expression following PPARa activation and determine whether constitutive activation of the skeletal muscle PPARa pathway leads to alterations in glucose utilization and insulin resistance in vivo. The long-term goals of these studies are to increase our understanding of the link between alterations in lipid metabolism and the development of diabetes and to identify potential targets of novel therapeutic interventions relevant to the treatment of insulin resistance and diabetes.
