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Endocrinology Vol. 143, No. 6 2106-2118
Copyright © 2002 by The Endocrine Society

INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS

Gene Expression Profile of Adipocyte Differentiation and Its Regulation by Peroxisome Proliferator-Activated Receptor-{gamma} Agonists

David L. Gerhold, Franklin Liu, Guoqiang Jiang, Zhihua Li, Jian Xu, Meiqing Lu, Jeffrey R. Sachs, Ansuman Bagchi, Arthur Fridman, Daniel J. Holder, Thomas W. Doebber, Joel Berger, Alex Elbrecht, David E. Moller and Bei B. Zhang

Departments of Molecular Endocrinology (F.L., G.J., Z.L., T.W.D., J.B., A.E., D.E.M., B.B.Z.), Pharmacology (D.L.G., J.X., M.L.), Applied Computer Science and Mathematics (J.R.S., A.B., A.F.), and Biometrics Research (D.J.H.), Merck Research Laboratories, Rahway, New Jersey 07065, and West Point, Pennsylvania 19486

Address all correspondence and requests for reprints to: Dr. Bei B. Zhang, R80W180, Merck Research Laboratories, P.O. Box 2000, 126 East Lincoln Avenue, Rahway, New Jersey 07065. E-mail: . bei_zhang{at}merck.com

PPAR{gamma} is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR{gamma}, such as thiazolidinediones (TZDs), promote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonucleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adipocytes and differentiating preadipocytes to a TZD PPAR{gamma} agonist in vitro. The expression of 579 genes was significantly up- or down-regulated by more than 1.5-fold during differentiation and/or by treatment with TZD, and these genes were organized into 32 clusters that demonstrated concerted changes in expression of genes controlling cell growth or lipid metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of ß-catenin as a new PPAR{gamma} target gene. Both mRNA and protein levels for ß-catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts and were further decreased by treatment of adipocytes with PPAR{gamma} agonists. Treatment of db/db mice with a PPAR{gamma} agonist also resulted in reduction of ß-catenin mRNA levels in adipose tissue. These results suggest that ß-catenin plays an important role in the regulation of adipogenesis. Thus, the transcriptional patterns revealed in this study further the understanding of adipogenesis process and the function of PPAR{gamma} activation.




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