文献类型：期刊文献

中文题名：7-Chloroarctinone-b as a new selective PPARy antagonist potently blocks adipocyte differentiation

英文题名：7-Chloroarctinone-b as a new selective PPARy antagonist potently blocks adipocyte differentiation

作者：Yong-tao LI[1];Li LI[1];Jing CHEN[2];Tian-cen HU[2];Jin HUANG[1];Yue-wei GUO[2];Hua-liang JIANG[1,2];Xu SHEN[1,2]

机构：[1]School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;[2]Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

年份：2009

卷号：30

期号：9

起止页码：1351

中文期刊名：Acta Pharmacologica Sinica

外文期刊名：中国药理学报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2011_2012】；PubMed;

基金：Acknowledgments 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.

语种：英文

中文关键词：peroxisome proliferator-activated receptor; antagonist; surface plasmon resonance; recruitment of the coactivator; adipocyte differentiation

外文关键词：peroxisome proliferator-activated receptor; antagonist; surface plasmon resonance; recruitment of the coactivator; adipocyte differentiation

摘要：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 PPARy antagonists with inhibitory effects on adipocyte differentiation. Methods： Surface plasmon resonance （SPR） technology and cell-based transactivation assay were used to screen for PPARy antago nists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARy/RXRγ heterodimerization and PPARy co-activator recruitment using yeast two-hybrid assay, Ga14/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 PPARy antagonist capable of inhibiting rosiglitazone-induced PPARy transcriptional activity. SPR analysis suggested that CAB bound tightly to PPARy and considerably antagonized the potent PPARy 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 rosiglitazoneinduced recruitment of the coactivator for PPARy. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture. Conclusion： CAB shows antagonistic activity to PPARy and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.
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 PPARy antagonists with inhibitory effects on adipocyte differentiation. Methods： Surface plasmon resonance （SPR） technology and cell-based transactivation assay were used to screen for PPARy antago nists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARy/RXRγ heterodimerization and PPARy co-activator recruitment using yeast two-hybrid assay, Ga14/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 PPARy antagonist capable of inhibiting rosiglitazone-induced PPARy transcriptional activity. SPR analysis suggested that CAB bound tightly to PPARy and considerably antagonized the potent PPARy 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 rosiglitazoneinduced recruitment of the coactivator for PPARy. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture. Conclusion： CAB shows antagonistic activity to PPARy and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.