Corepressors selectively control the transcriptional activity of PPARγ in adipocytes

HP Guan, T Ishizuka, PC Chui, M Lehrke… - Genes & …, 2005 - genesdev.cshlp.org
HP Guan, T Ishizuka, PC Chui, M Lehrke, MA Lazar
Genes & development, 2005genesdev.cshlp.org
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of
adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many
PPARγ 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 PPARγ ligand is selectively
required for adipocyte gene expression. The GyK gene contains a functional PPARγ …
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPARγ 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 PPARγ ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPARγ-response element to which endogenous PPARγ is recruited in adipocytes. However, unlike the classic PPARγ-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 PPARγ-Coactivator 1α (PGC-1α), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPARγ target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms.
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