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Proc Natl Acad Sci U S A. 1999 May 25;96(11):6102-6.

A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.

Author information

  • 1Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709, USA.

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.

PMID:
10339548
[PubMed - indexed for MEDLINE]
PMCID:
PMC26842
Free PMC Article
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