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Endocrinology Vol. 142, No. 7 3207-3213
Copyright © 2001 by The Endocrine Society

ARTICLES

A Novel Potent Antagonist of Peroxisome Proliferator-Activated Receptor {gamma} Blocks Adipocyte Differentiation But Does Not Revert the Phenotype of Terminally Differentiated Adipocytes

Heidi S. Camp, Archana Chaudhry and Todd Leff

Department of Cell Biology and Endocrinology, Pfizer Global Research and Development (H.S.C., A.C., T.L.), and Department of Biological Chemistry, University of Michigan Medical School (T.L.), Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: Heidi S. Camp, Department of Cell Biology and Endocrinology, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105. E-mail: Heidi.Camp{at}pfizer.com

The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}). Their antihyperglycemic effects seem to be linked to the regulation of PPAR{gamma}-responsive genes. Here, we report the characterization of a specific PPAR{gamma} antagonist that blocks several of the biological activities of the PPAR{gamma} agonist rosiglitazone. PD068235 inhibited rosiglitazone-dependent PPAR{gamma} transcriptional activity with an IC50 of 0.8 µM and rosiglitazone-stimulated in vitro coactivator association. The role of PPAR{gamma} in the initiation of differentiation is well documented. In this study, we used PD068235 as a tool to evaluate the functional role of PPAR{gamma} in the maintenance of the terminally differentiated state. Treatment of confluent, growth-arrested 3T3-L1 preadipocytes with PD068235 blocked adipocyte differentiation induced by the standard adipogenic hormonal mixture (insulin/dexamethasone/isobutylmethylxanthin) and fully antagonized rosiglitazone-induced adipogenesis. In contrast, long-term treatment of terminally differentiated 3T3-L1 adipocytes with PD068235 did not induce any obvious morphological changes and had no effect on basal lipolysis rates. In addition, in fully differentiated adipocytes PD068235 did not alter the basal expression of PPAR{gamma} target genes aP2 and CAP, but it effectively blocked rosiglitazone-induced expression of both genes. These results suggest that in terminally differentiated adipocytes, the PPAR{gamma} activity is minimal and may not be required for the maintenance of PPAR{gamma} target gene expression.




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