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A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation

By Jennifer L. Oberfield, Jon L. Collins, Christopher P. Holmes, Donna M. Goreham, Joel P. Cooper, Jeffery E. Cobb, James M. Lenhard, Emily A. Hull-Ryde, Christopher P. Mohr, Steven G. Blanchard, Derek J. Parks, Linda B. Moore, Jürgen M. Lehmann, Kelli Plunket, Ann B. Miller, Michael V. Milburn, Steven A. Kliewer and Timothy M. Willson

Abstract

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

Topics: Biological Sciences
Publisher: The National Academy of Sciences
Year: 1999
OAI identifier: oai:pubmedcentral.nih.gov:26842
Provided by: PubMed Central
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