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.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the Korean Science and Engineering Foundation (KOSEF) funded by Ministry of Education, Science and Technology (MEST) [Grants M104KH010001-06K0801-00111, 20090091913, 20100001492, SC-3230]; and by the Ministry of Education and Human Resources Development [BK21 Research Fellowship (to H.W.J., J.-W.L., W.S.K., S.S.C., H.J.S.)].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.065748.
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ABBREVIATIONS:
- FFA
- free fatty acid
- TZD
- thiazolidinedione
- PPAR
- peroxisome proliferator-activated receptor
- LBD
- ligand-binding domain
- WY14643
- pirinixic acid
- GW501516
- 2-[2-methyl-4-([4-methyl-2-[4-(trifluoromethyl)phenyl)-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid
- CG301360
- (R)-1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid
- TNF
- tumor necrosis factor
- LPS
- lipopolysaccharide
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- HEK
- human embryonic kidney
- DMEM
- Dulbecco's modified Eagle's medium
- PDB
- Protein Data Bank
- qRT-PCR
- quantitative real-time polymerase chain reaction
- TG
- triacylglyceride
- ALT
- alanine aminotransferase
- AST
- aspartate aminotransferase
- TBST
- Tris-buffered saline with 0.1% Tween 20
- WAT
- white adipose tissue
- FGF21
- fibroblast growth factor 21
- siRNA
- small interfering RNA.
- Received April 21, 2010.
- Accepted August 19, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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