Role of AMP kinase and PPARδ in the regulation of lipid and glucose metabolism in human skeletal muscle

The peroxisome proliferator-activated receptor (PPAR)delta has been implicated in the regulation of lipid metabolism in skeletal muscle. Furthermore, activation of PPAR delta has been proposed to improve insulin sensitivity and reduce glucose levels in animal models of type 2 diabetes. We recently demonstrated that the PPAR delta agonist GW501516 activates AMP-activated protein kinase ( AMPK) and stimulates glucose uptake in skeletal muscle. However, the underlying mechanism remains to be clearly identified. In this study, we first confirmed that incubation of primary cultured human muscle cells with GW501516 induced AMPK phosphorylation and increased fatty acid transport and oxidation and glucose uptake. Using small interfering RNA, we have demonstrated that PPAR delta expression is required for the effect of GW501516 on the intracellular accumulation of fatty acids. Furthermore, we have shown that the subsequent increase in fatty acid oxidation induced by GW501516 is dependenton both PPAR delta and AMPK. Concomitant with these metabolic changes, we provide evidence that GW501516 increases the expression of key genes involved inlipid metabolism(FABP3, CPT1, and PDK4) by a PPAR delta-dependent mechanism. Finally, we have also demonstrated that the GW501516-mediated increase in glucose uptake requires AMPK but not PPAR alpha. In conclusion, the PPAR delta agonist GW501516 promotes changes in lipid/glucose metabolism and gene expression in human skeletal muscle cells by PPAR delta- and AMPK-dependent and -independent mechanisms.