title: 7-Chloroarctinone-b as a new selective PPARgamma antagonist potently blocks adipocyte differentiation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yong-tao
authors.initials: YT
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Tian-cen
authors.initials: TC
authors.lastname: Hu
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Yue-wei
authors.initials: YW
authors.lastname: Guo
authors.forename: Hua-liang
authors.initials: HL
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D041721:3T3-L1 Cells / Q000187:drug effects; D017667:Adipocytes / Q000187:drug effects*; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D020349:Surface Plasmon Resonance; D013876:Thiophenes / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D020798:Two-Hybrid System Techniques
chemical_list: C544871:7-chloroarctinone-b; D047495:PPAR gamma; D013876:Thiophenes
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