PGC-1 and Muscle Mitochondrial Dysfunction in Diabetes

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DESCRIPTION (provided by applicant): Insulin resistance characterizes skeletal muscle from patients with obesity and type 2 diabetes mellitus and is widely considered to be an important factor in the pathogenesis of type 2 diabetes. Recently, it has become appreciated that mitochondrial dysfunction in skeletal muscle is found in tandem with insulin resistance. These mitochondrial abnormalities include defects in Krebs cycle activity, electron transport, oxidative capacity, and selection of oxidative fuel (carbohydrate vs. fat). A body of evidence is accumulating suggesting that intramyocellular lipids, including triglycerides, fatty acids (FFA), fatty acyI-CoAs, and ceramides inhibit insulin receptor signaling and cause insulin resistance. Taken together, these findings lead to the overall hypothesis that decreased capacity of muscle mitochondria to oxidize fatty acids leads to an accumulation of various fatty acid metabolites that in turn inhibit insulin receptor signaling and insulin action. Up to this point, the mechanism of decreased mitochondrial oxidative capacity in insulin resistant muscle has been unclear. We present evidence indicating that decreased expression of peroxisome proliferator activated receptor (PPAR)-gamma coactivator-1 (PGC-1) and nuclear respiratory factor (NRF)-1 in insulin resistant muscle is responsible for a coordinate reduction of expression of a wide array of nuclear-encoded mitochondrial genes involved in electron transport and oxidative phosphorylation. In this project we will determine whether changes in PGC-1 and/or NRF-1 expression in skeletal muscle predict the direction of changes in expression of nuclear-encoded mitochondrial genes, mitochondrial function, and lipid content and insulin receptor signaling in skeletal muscle. Specifically, we propose: 1) To determine whether an experimental increase in plasma FFA concentrations using a lipid infusion that decreases PGC-1/NRF-1 expression in muscle also decreases expression of nuclear-encoded mitochondrial genes and increases intramyocellular triglyceride, fatty acyl CoA, and ceramide concentrations. 2) To determine whether an experimental decrease in plasma FFA using Acipimox treatment increases PGC-1/NRF-1 expression in concert with increased expression of nuclear encoded mitochondrial genes. 3) To determine whether physical exercise (muscle contraction) increases PGC-1 and NRF-1 expression in muscle of insulin resistant subjects. 4) To determine whether treatment with a PPAR-gamma agonist increases PGC-1/NRF-1 expression in skeletal muscle from insulin resistant patients. We will test the hypothesis that a PPAR-gamma agonist-induced increase in PGC-1/NRF-1 expression predicts increased expression of nuclear-encoded mitochondrial genes and decreased intramyocellular triglyceride, fatty acyl CoA, and ceramide concentrations. 5) To determine whether common single nucleotide polymorphisms in the PGC-1 gene are associated with decreased PGC-1 expression or insulin resistance in Mexican Americans.