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RESEARCH PAPER
in adipocytes
Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine, Genetics, and Pharmacology, and The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Peroxisome proliferator-activated receptor 
(PPAR) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPAR target genes are induced during adipogenesis, but others, such as glycerol kinase (GyK), are expressed at low levels in adipocytes and dramatically up-regulated by TZDs. Here, we have explored the mechanism whereby an exogenous PPAR ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPAR-response element to which endogenous PPAR is recruited in adipocytes. However, unlike the classic PPAR-target gene aP2, which is constitutively associated with coactivators, the GyK gene is targeted by nuclear receptor corepressors in adipocytes. TZDs trigger the dismissal of corepressor histone deacetylase (HDAC) complexes and the recruitment of coactivators to the GyK gene. TZDs also induce PPAR-Coactivator 1
(PGC-1), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPAR target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms.
[Keywords: PPAR; corepressor; TZD; adipocyte]
Received September 20, 2004; revised version accepted December 17, 2004.
E-MAIL lazar{at}mail.med.upenn.edu; FAX (215) 898-5408.
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