A Peroxisome Proliferator-Activated Receptor γ Ligand Inhibits Adipocyte Differentiation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 11; pp. 6102 - 6106
• Main Authors: Oberfield, Jennifer L., Collins, Jon L., Holmes, Christopher P., Goreham, Donna M., Cooper, Joel P., Cobb, Jeffery E., Lenhard, James M., Hull-Ryde, Emily A., Mohr, Christopher P., Blanchard, Steven G., Parks, Derek J., Moore, Linda B., Lehmann, Jürgen M., Plunket, Kelli, Miller, Ann B., Milburn, Michael V., Kliewer, Steven A., Willson, Timothy M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 25.05.1999; National Acad Sciences; The National Academy of Sciences
• Subjects: Adipocytes; Adipocytes - cytology; Agonists; Animals; Binding Sites; Biochemistry; Biological Sciences; Cell culture techniques; Cell Differentiation - drug effects; Cell Line; Chlorocebus aethiops; Co repressor proteins; Crystallography, X-Ray; Humans; Kinetics; Ligands; Mice; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Multipotent stem cells; Nuclear Proteins - metabolism; Plasmids; Protein Structure, Secondary; Receptors; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - genetics; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Rosiglitazone; Stem cells; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Thiazolidinediones; Thiazolidines; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - genetics; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.11.6102

The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARγ 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 PPARγ ligand that was a weak partial agonist of PPARγ 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.