Pharmacological Activation of Peroxisome Proliferator-activated Receptor δ Improves Insulin Resistance and Hepatic Steatosis in High Fat Diet-induced Diabetic Mice

The mechanisms regarding hepatic steatosis related to hepatic insulin resistance have been well documented. However, the agents for treatment of hepatic steatosis and insulin resistance remain poorly developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that are responsible for the regulation of glucose and/or lipid metabolism. There are 3 distinct isoforms of PPARs family: PPAR alpha, PPAR gamma, and PPAR delta. Both PPAR alpha and PPAR gamma agonists are widely used in clinic for the treatment of hyperlipidemia and hyperglycemia. However, the therapeutic efficacy of PPAR delta agonists for diabetic disorders remains obscure. In the present study, we used L-165041 as PPAR delta agonist to treat the high fat diet (HFD) fed mice. Administration of L-165041 improved the hepatic steatosis and increased the insulin sensitivity in HFD-mice. In addition to the histological identification of hepatic steatosis, the improvement of insulin sensitivity was characterized by the enhanced insulin signals and the increase of hepatic glycogen content. This is the first report showing that pharmacological activation of PPAR delta improves insulin resistance in diet-induced diabetic mice. Thus, we suggest that pharmacological activation of PPAR delta may be a new strategy for the treatment of diabetic patients with hepatic steatosis.