TY - JOUR T1 - A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist CG301360 Alleviates Insulin Resistance and Lipid Dysregulation in <em>db/db</em> Mice JF - Molecular Pharmacology JO - Mol Pharmacol SP - 877 LP - 885 DO - 10.1124/mol.110.065748 VL - 78 IS - 5 AU - Hyun Woo Jeong AU - Joo-Won Lee AU - Woo Sik Kim AU - Sung Sik Choe AU - Hyun Jung Shin AU - Gha Young Lee AU - Dongkyu Shin AU - Jun Hee Lee AU - Eun Bok Choi AU - Hyun Kyu Lee AU - Gyu Hwan Yon AU - Bongjun Cho AU - Hye Ryung Kim AU - Sung Hee Choi AU - Young Sun Chung AU - Seung Bum Park AU - Heekyoung Chung AU - Seonggu Ro AU - Jae Bum Kim Y1 - 2010/11/01 UR - http://molpharm.aspetjournals.org/content/78/5/877.abstract N2 - Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPARα agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPARγ 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 PPARα/γ dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPARα/γ dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPARα/γ 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 PPARα and PPARγ and induced expression of their target genes in a PPARα- and PPARγ-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 PPARα/γ agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia. ER -