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)-κB activation as a result of diacylglycerol (DAG) accumulation and subsequent protein kinase Cθ (PKCθ) phosphorylation. At present, it is unknown whether peroxisome proliferator-activated receptor-δ (PPARδ) activation prevents fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. In C2C12 skeletal muscle cells, the PPARδ agonist GW501516 prevented phosphorylation of insulin receptor substrate-1 at Ser307 and the inhibition of insulin-stimulated Akt phosphorylation caused by exposure to the saturated fatty acid palmitate. This latter effect was reversed by the PPARδ antagonist GSK0660. Treatment with the PPARδ agonist enhanced the expression of two well known PPARδ 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 PKCθ 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, PPARδ activation by GW501516 blocked palmitate-induced NF-κB 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 PPARδ attenuates fatty acid-induced NF-κB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Our results point to PPARδ activation as a pharmacological target to prevent insulin resistance.
Genetic downregulation of receptor-interacting protein 140 uncovers the central role of Akt signalling in the regulation of fatty acid oxidation in skeletal muscle cells