Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes.
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.
Guan
Hong-Ping
HP
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
T
Chui
Patricia C
PC
Lehrke
Michael
M
Lazar
Mitchell A
MA
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005991:Glycerol Kinase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000378:metabolism / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011485:Protein Binding; D012097:Repressor Proteins / Q000502:physiology*; D012689:Sequence Homology, Nucleic Acid; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D017931:DNA Primers; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012097:Repressor Proteins; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; C089946:2,4-thiazolidinedione; D005991:Glycerol Kinase