RT Journal Article SR Electronic T1 A Non-TZD PPARα/γ Dual Agonist CG301360 Alleviates Insulin Resistance and Lipid Dysregulation in db/db Mice JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.110.065748 DO 10.1124/mol.110.065748 A1 Hyun Woo Jeong A1 Joo-Won Lee A1 Woo Sik Kim A1 Sung Sik Choe A1 Hyun Jung Shin A1 Gha Young Lee A1 Dongkyu Shin A1 Jun Hee Lee A1 Eun Bok Choi A1 Hyun Kyu Lee A1 Gyu Hwan Yon A1 Bongjun Cho A1 Hye Ryung Kim A1 Sung Hee Choi A1 Young Sun Chung A1 Seung Bum Park A1 Heekyung Chung A1 Seonggu Ro A1 Jae Bum Kim YR 2010 UL http://molpharm.aspetjournals.org/content/early/2010/08/19/mol.110.065748.abstract AB 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, while 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, 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.