A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation.
While searching for natural ligands for the peroxisome proliferator-activated receptor (PPAR) gamma, we identified a synthetic compound that binds to this receptor. Bisphenol A diglycidyl ether (BADGE) is a ligand for PPARgamma with a K(d(app)) of 100 microM. This compound has no apparent ability to activate the transcriptional activity of PPARgamma; however, BADGE can antagonize the ability of agonist ligands such as rosiglitazone to activate the transcriptional and adipogenic action of this receptor. BADGE also specifically blocks the ability of natural adipogenic cell lines such as 3T3-L1 and 3T3-F442A cells to undergo hormone-mediated cell differentiation. These results provide the first pharmacological evidence that PPARgamma activity is required for the hormonally induced differentiation of adipogenic cells.
Wright
H M
HM
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Clish
C B
CB
Mikami
T
T
Hauser
S
S
Yanagi
K
K
Hiramatsu
R
R
Serhan
C N
CN
Spiegelman
B M
BM
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D001559:Benzhydryl Compounds; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D005938:Glucocorticoids / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D000098826:Bisphenol A Compounds
D015056:1-Methyl-3-isobutylxanthine; D001559:Benzhydryl Compounds; D003907:Dexamethasone; D004852:Epoxy Compounds; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D007328:Insulin; D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D000077154:Rosiglitazone; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds