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Acta Pharmacol Sin. 2009 Sep;30(9):1351-8. doi: 10.1038/aps.2009.113. Epub 2009 Aug 17.

7-Chloroarctinone-b as a new selective PPARgamma antagonist potently blocks adipocyte differentiation.

Author information

1
School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

Abstract

AIM:

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a therapeutic target for obesity, cancer and diabetes mellitus. In order to develop potent lead compounds for obesity treatment, we screened a natural product library for novel PPARgamma antagonists with inhibitory effects on adipocyte differentiation.

METHODS:

Surface plasmon resonance (SPR) technology and cell-based transactivation assay were used to screen for PPARgamma antagonists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARgamma/RXRalpha heterodimerization and PPARgamma co-activator recruitment using yeast two-hybrid assay, Gal4/UAS cell-based assay and SPR based assay. The 3T3-L1 cell differentiation assay was used to evaluate the effect of the active compound on adipocyte differentiation.

RESULTS:

A new thiophene-acetylene type of natural product, 7-chloroarctinone-b (CAB), isolated from the roots of Rhaponticum uniflorum, was discovered as a novel PPARgamma antagonist capable of inhibiting rosiglitazone-induced PPARgamma transcriptional activity. SPR analysis suggested that CAB bound tightly to PPARgamma and considerably antagonized the potent PPARgamma agonist rosiglitazone-stimulated PPARgamma-LBD/RXRalpha-LBD binding. Gal4/UAS and yeast two-hybrid assays were used to evaluate the antagonistic activity of CAB on rosiglitazone-induced recruitment of the coactivator for PPARgamma. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture.

CONCLUSION:

CAB shows antagonistic activity to PPARgamma and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.

PMID:
19684608
PMCID:
PMC4007185
DOI:
10.1038/aps.2009.113
[Indexed for MEDLINE]
Free PMC Article

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