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© 2002 by the American Diabetes Association, Inc.
Peroxisome Proliferator-Activated Receptor-
Regulates Fatty Acid Utilization in Primary Human Skeletal Muscle Cells
1 Department of Medicine and Cell Biology, Duke University Medical Center, Durham, North Carolina
2 Department of Biochemistry and the Human Performance Laboratory, East Carolina University, Greenville, North Carolina
3 Departments of Molecular Endocrinology and Metabolic Diseases, GlaxoSmithKline, Research Triangle Park, North Carolina
In humans, skeletal muscle is a major site of peroxisome proliferator–activated receptor-
(PPAR-) expression, but its function in this tissue is unclear. We investigated the role of hPPAR- in regulating muscle lipid utilization by studying the effects of a highly selective PPAR- agonist, GW7647, on [14C]oleate metabolism and gene expression in primary human skeletal muscle cells. Robust induction of PPAR- protein expression occurred during muscle cell differentiation and corresponded with differentiation-dependent increases in oleate oxidation. In mature myotubes, 48-h treatment with 10–1,000 nmol/l GW7647 increased oleate oxidation dose-dependently, up to threefold. Additionally, GW7647 decreased oleate esterification into myotube triacylglycerol (TAG), up to 45%. This effect was not abolished by etomoxir, a potent inhibitor of ß-oxidation, indicating that PPAR-–mediated TAG depletion does not depend on reciprocal changes in fatty acid catabolism. Consistent with its metabolic actions, GW7647 induced mRNA expression of mitochondrial enzymes that promote fatty acid catabolism; carnitine palmityltransferase 1 and malonyl-CoA decarboxylase increased 
2-fold, whereas pyruvate dehydrogenase kinase 4 increased 45-fold. Expression of several genes that regulate glycerolipid synthesis was not changed by GW7647 treatment, implicating involvement of other targets to explain the TAG-depleting effect of the compound. These results demonstrate a role for hPPAR- in regulating muscle lipid homeostasis.
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