title: A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.
abstract: The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARgamma ligand that was a weak partial agonist of PPARgamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.
authors.affiliation: Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Oberfield
authors.forename: J L
authors.initials: JL
authors.lastname: Collins
authors.forename: C P
authors.initials: CP
authors.lastname: Holmes
authors.forename: D M
authors.initials: DM
authors.lastname: Goreham
authors.forename: J P
authors.initials: JP
authors.lastname: Cooper
authors.forename: J E
authors.initials: JE
authors.lastname: Cobb
authors.forename: J M
authors.initials: JM
authors.lastname: Lenhard
authors.forename: E A
authors.initials: EA
authors.lastname: Hull-Ryde
authors.forename: C P
authors.initials: CP
authors.lastname: Mohr
authors.forename: S G
authors.initials: SG
authors.lastname: Blanchard
authors.forename: D J
authors.initials: DJ
authors.lastname: Parks
authors.forename: L B
authors.initials: LB
authors.lastname: Moore
authors.forename: J M
authors.initials: JM
authors.lastname: Lehmann
authors.forename: K
authors.initials: K
authors.lastname: Plunket
authors.forename: A B
authors.initials: AB
authors.lastname: Miller
authors.forename: M V
authors.initials: MV
authors.lastname: Milburn
authors.forename: S A
authors.initials: SA
authors.lastname: Kliewer
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D000077154:Rosiglitazone; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D014162:Transfection
chemical_list: C119543:GW0072; D008024:Ligands; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors; D000077154:Rosiglitazone