This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is associated with insulin resistance and increased lipid accumulation in skeletal muscle, pancreas, and liver, with resulting functional impairment that has been called lipotoxicity. The factors leading to ectopic lipid accumulation and the best intervention to reverse this pathophysiology are not clear. We will examine insulin sensitivity, intramyocellular fat content, adipokines secretion and changed in the pattern of gene expression in subjects with impaired glucose tolerance in response to different PPAR ligands. We propose that PPAR a ligand (fenofibrate) and PPAR ? ligand (pioglitazone) will reduce muscle lipid accumulation by stimulating muscle lipid oxidation and redistribution of lipid from muscle to adipocytes respectively. The combination of both medications will be particularly effective at reducing muscle lipid accumulation. These studies are designed to examine fundamental clinical mechanisms underlying the metabolic syndrome and diabetes.
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