A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor alpha/gamma Dual Agonist CG301360 Alleviates Insulin Resistance and Lipid Dysregulation in db/db Mice

Abstract

Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPAR alpha agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPAR gamma agonists regulate lipid redistribution from visceral fat to subcutaneous fat and enhance insulin sensitivity. To achieve combined benefits from activated PPARs on lipid metabolism and insulin sensitivity, a number of PPAR alpha/gamma dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPAR alpha/gamma dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPAR alpha/gamma dual agonist, (R)-1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid (CG301360), exhibiting the improvement in insulin sensitivity and lipid metabolism. CG301360 selectively stimulated transcriptional activities of PPAR alpha and PPAR gamma and induced expression of their target genes in a PPAR alpha- and PPAR gamma-dependent manner. In cultured cells, CG301360 enhanced fatty acid oxidation and glucose uptake and it reduced pro-inflammatory gene expression. In db/db mice, CG301360 also restored insulin sensitivity and lipid homeostasis. Collectively, these data suggest that CG301360 would be a novel PPAR alpha/gamma agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.