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Differential Gene Regulation by PPAR Agonist and Constitutively Active PPAR2

Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Mitchell A. Lazar, M.D., Ph.D., University of Pennsylvania School of Medicine, 611 Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149. E-mail: lazar{at}mail.med.upenn.edu.

The PPAR is a key adipogenic determination factor. Ligands for PPAR such as antidiabetic thiazolidinedione (TZD) compounds are adipogenic, and many adipocyte genes that are activated by TZDs contain binding sites for PPAR. Like ligands for other nuclear receptors, TZDs can regulate genes positively or negatively. Here, we sought to understand the importance of positive regulation of gene expression by PPAR in adipogenesis. Fusion of the potent viral transcriptional activator VP16 to PPAR2 (VP16-PPAR) created a transcription factor that constitutively and dramatically activated transcription of PPAR-responsive genes in the absence of ligand. Forced expression of VP16-PPAR in 3T3-L1 preadipocytes using retroviral vectors led to adipogenesis in the absence of standard differentiating medium or any exogenous PPAR ligand. Gene microarray analysis revealed that VP16-PPAR induced many of the genes associated with adipogenesis and adipocyte function. Thus, direct up-regulation of gene expression by PPAR is sufficient for adipogenesis. TZD-induced adipogenesis up-regulated many of the same genes, although some were divergently regulated, including resistin, whose gene expression was reduced inVP16-PPAR adipocytes treated with TZDs. These results show that, although activation of PPAR by a heterologous activation domain is sufficient for adipogenesis, it is not equivalent to TZD treatment. This conclusion has important implications for understanding biological effects of the TZDs on adipogenesis and insulin sensitization.

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