title: A nonthiazolidinedione peroxisome proliferator-activated receptor α/γ 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; 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.
authors: School of Biological Sciences, Seoul National University, Kwanak-Gu, Seoul, Korea.
authors: Hyun Woo
authors: HW
authors: Jeong
authors: Joo-Won
authors: JW
authors: Lee
authors: Woo Sik
authors: WS
authors: Kim
authors: Sung Sik
authors: SS
authors: Choe
authors: Hyun Jung
authors: HJ
authors: Shin
authors: Gha Young
authors: GY
authors: Lee
authors: Dongkyu
authors: D
authors: Shin
authors: Jun Hee
authors: JH
authors: Lee
authors: Eun Bok
authors: EB
authors: Choi
authors: Hyun Kyu
authors: HK
authors: Lee
authors: Gyu Hwan
authors: GH
authors: Yon
authors: Bongjun
authors: B
authors: Cho
authors: Hye Ryung
authors: HR
authors: Kim
authors: Sung Hee
authors: SH
authors: Choi
authors: Young Sun
authors: YS
authors: Chung
authors: Seung Bum
authors: SB
authors: Park
authors: Heekyoung
authors: H
authors: Chung
authors: Seonggu
authors: S
authors: Ro
authors: Jae Bum
authors: JB
authors: Kim
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008820:Mice, Obese; D010080:Oxazoles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists* / Q000502:physiology; D047494:PPAR delta / Q000819:agonists* / Q000502:physiology; D010875:Pipecolic Acids / Q000494:pharmacology*; D013237:Stereoisomerism; D014158:Transcription, Genetic
chemical_list: C553922:1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid; D016207:Cytokines; D005227:Fatty Acids; D010080:Oxazoles; D047493:PPAR alpha; D047494:PPAR delta; D010875:Pipecolic Acids; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D005947:Glucose