A nonthiazolidinedione peroxisome proliferator-activated receptor α/γ dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db mice

• Published in: Molecular pharmacology 2010-11, Vol.78 (5), p.877-885
• Main Authors: Jeong, Hyun Woo, Lee, Joo-Won, Kim, Woo Sik, Choe, Sung Sik, Shin, Hyun Jung, Lee, Gha Young, Shin, Dongkyu, Lee, Jun Hee, Choi, Eun Bok, Lee, Hyun Kyu, Yon, Gyu Hwan, Cho, Bongjun, Kim, Hye Ryung, Choi, Sung Hee, Chung, Young Sun, Park, Seung Bum, Chung, Heekyoung, Ro, Seonggu, Kim, Jae Bum
• Format: Article
• Language: English
• Subjects: Adipocytes - drug effects; Adipocytes - metabolism; Animals; Cells, Cultured; Cyclooxygenase 2 - biosynthesis; Cytokines - biosynthesis; Fatty Acids - metabolism; Gene Expression Regulation - drug effects; Glucose - metabolism; Insulin Resistance; Lipid Metabolism - drug effects; Macrophages - drug effects; Macrophages - metabolism; Matrix Metalloproteinase 9 - biosynthesis; Mice; Mice, Obese; Oxazoles - pharmacology; Oxidation-Reduction; Pipecolic Acids - pharmacology; PPAR alpha - agonists; PPAR alpha - physiology; PPAR delta - agonists; PPAR delta - physiology; Stereoisomerism; Transcription, Genetic
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.110.065748

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.