Enhancement of insulin signaling through inhibition of tissue lipid accumulation by activation of peroxisome proliferator-activated receptor (PPAR) alpha in obese mice.

The aim of the present study was to investigate the effect of PPARalpha activation on insulin signaling and lipid accumulation in the liver and skeletal muscle of insulin-resistant (ob/ob) mice. A known subtype-selective PPARalpha agonist, Wy-14,643, was administered to lean and ob/ob mice at 30 mg/kg/day for 4 weeks. Insulin (100 units/kg) or saline was injected into the portal vein of anesthetized mice. The liver and skeletal muscles were used for the detection of tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrates (IRSs), as well as for the determination of both IRS-associated PI3-K activity and lipid content; in addition, the measurement of mRNA levels of PPAR-regulated genes was carried out. The PPARalpha agonist lowered plasma levels of glucose, insulin, triglycerides, and free fatty acids in ob/ob mice. Several PPARalpha-upregulated genes related to the transport and oxidation of fatty acids in the liver were increased by treatment with the agonist. The PPARalpha agonist significantly increased IR- and IRS-tyrosine phosphorylation and IRS-associated PI3-K activity in the liver and muscle of ob/ob mice, without exerting the same effects in lean mice. Moreover, these effects in ob/ob mice were accompanied by decreased triglyceride and fatty acyl-CoA contents in the liver and skeletal muscle. The present results suggest that inhibition of lipid accumulation by hepatic PPARalpha activation leads to an improvement in impaired insulin signaling in muscle tissue as well as in the liver of insulin-resistant mice.