Abstract
Aim:
Peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ antagonists with inhibitory effects on adipocyte differentiation.
Methods:
Surface plasmon resonance (SPR) technology and cell-based transactivation assay were used to screen for PPARγ antagonists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARγ/RXRα heterodimerization and PPARγ 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 PPARγ antagonist capable of inhibiting rosiglitazone-induced PPARγ transcriptional activity. SPR analysis suggested that CAB bound tightly to PPARγ and considerably antagonized the potent PPARγ agonist rosiglitazone-stimulated PPARγ-LBD/RXRα-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 PPARγ. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture.
Conclusion:
CAB shows antagonistic activity to PPARγ and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.
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Acknowledgements
This work was supported by the National High Technology Research and Development Program of China (2006AA09Z447), National Natural Science Foundation of China (grants 30890044, 90713046, 20721003), Shanghai Pujiang Program PJ200700247.
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Li, Yt., Li, L., Chen, J. et al. 7-Chloroarctinone-b as a new selective PPARγ antagonist potently blocks adipocyte differentiation. Acta Pharmacol Sin 30, 1351–1358 (2009). https://doi.org/10.1038/aps.2009.113
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DOI: https://doi.org/10.1038/aps.2009.113
