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PMID: 15681609 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes.

Genes & development ·Vol. 19 ·No. 4 ·2005-02-15 ·Pages 453-61

Guan HP, Ishizuka T, Chui PC, Lehrke M, Lazar MA

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPARgamma 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 PPARgamma ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPARgamma-response element to which endogenous PPARgamma is recruited in adipocytes. However, unlike the classic PPARgamma-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 PPARgamma-Coactivator 1alpha (PGC-1alpha), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPARgamma target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms.

MeSH Terms
3T3-L1 Cells Adipocytes/enzymology,physiology Animals Base Sequence DNA Primers Glycerol Kinase/genetics,metabolism Mice Molecular Sequence Data PPAR gamma/metabolism,physiology Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Protein Binding Repressor Proteins/physiology Sequence Homology, Nucleic Acid Thiazolidinediones/pharmacology Trans-Activators/biosynthesis Transcription Factors Transcription, Genetic/drug effects,physiology
Chemicals
DNA Primers PPAR gamma Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Repressor Proteins Thiazolidinediones Trans-Activators Transcription Factors 2,4-thiazolidinedione Glycerol Kinase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Guan Hong-Ping
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Ishizuka Takahiro
Chui Patricia C
Lehrke Michael
Lazar Mitchell A
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1263305
Published
2005-02-15
Epub
2005-00-28
Pages
453-61
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC548946
Subset
IM
Grants
NIDDK NIH HHS · R01 DK049780 · United States
Corrections
CommentIn
PMID: 15713837
External Links
PubMed source DOI: 10.1101/gad.1263305 PMC Full Text View journal details
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