A nonthiazolidinedione peroxisome proliferator-activated receptor α/γ dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db mice.
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.
Jeong
Hyun Woo
HW
School of Biological Sciences, Seoul National University, Kwanak-Gu, Seoul, Korea.
Lee
Joo-Won
JW
Kim
Woo Sik
WS
Choe
Sung Sik
SS
Shin
Hyun Jung
HJ
Lee
Gha Young
GY
Shin
Dongkyu
D
Lee
Jun Hee
JH
Choi
Eun Bok
EB
Lee
Hyun Kyu
HK
Yon
Gyu Hwan
GH
Cho
Bongjun
B
Kim
Hye Ryung
HR
Choi
Sung Hee
SH
Chung
Young Sun
YS
Park
Seung Bum
SB
Chung
Heekyoung
H
Ro
Seonggu
S
Kim
Jae Bum
JB
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
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