Activation of Peroxisome Proliferator-Activated Receptor-δ by GW501516 Prevents Fatty Acid-Induced Nuclear Factor-κB Activation and Insulin Resistance in Skeletal Muscle Cells

Elevated plasma free fatty acids cause insulin resistance in skeletal muscle through the activation of a chronic inflammatory process. This process involves nuclear factor (NF)-kappa B activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase C theta (PKC theta) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-delta (PPAR delta) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPAR delta agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser(307) and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPAR delta antagonist GSK0660. Treatment with the PPAR delta agonist enhanced the expression of two well known PPAR delta target genes involved in fatty acid oxidation, carnitine palmitoyltransferase-1 and pyruvate dehydrogenase kinase 4 and increased the phosphorylation of AMP-activated protein kinase, preventing the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKC theta activation caused by palmitate. These effects were abolished in the presence of the carnitine palmitoyltransferase-1 inhibitor etomoxir, thereby indicating that increased fatty acid oxidation was involved in the changes observed. Consistent with these findings, PPAR delta activation by GW501516 blocked palmitate-induced NF-kappa B DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 and human skeletal muscle cells as well as the protein secretion of this cytokine. These findings indicate that PPAR delta attenuates fatty acid-induced NF-kappa B activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPAR delta activation as a pharmacological target to prevent insulin resistance. (Endocrinology 151: 1560-1569, 2010)