A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation

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, Timothy M. Willson

Research output: Contribution to journalArticle

299 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6102-6106
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number11
DOIs
StatePublished - May 25 1999

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Peroxisome Proliferator-Activated Receptors
Adipocytes
Ligands
Adipogenesis
X Ray Crystallography
Cytoplasmic and Nuclear Receptors
Hypoglycemic Agents
Transcriptional Activation
Epitopes
Homeostasis
Cell Culture Techniques
Lipids
Glucose
GW0072

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Oberfield, J. L., Collins, J. L., Holmes, C. P., Goreham, D. M., Cooper, J. P., Cobb, J. E., ... Willson, T. M. (1999). A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America, 96(11), 6102-6106. https://doi.org/10.1073/pnas.96.11.6102

A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 11, 25.05.1999, p. 6102-6106.

Research output: Contribution to journalArticle

Oberfield, JL, Collins, JL, Holmes, CP, Goreham, DM, Cooper, JP, Cobb, JE, Lenhard, JM, Hull-Ryde, EA, Mohr, CP, Blanchard, SG, Parks, DJ, Moore, LB, Lehmann, JM, Plunket, K, Miller, AB, Milburn, MV, Kliewer, SA & Willson, TM 1999, 'A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 11, pp. 6102-6106. https://doi.org/10.1073/pnas.96.11.6102
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. / A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 11. pp. 6102-6106.
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