TAZ Is a Negative Regulator of PPARγ Activity in Adipocytes and TAZ Deletion Improves Insulin Sensitivity and Glucose Tolerance

Dalila El Ouarrat, Roi Isaac, Yun Sok Lee, Da Young Oh, Joshua Wollam, Denise Lackey, Matthew Riopel, Gautam Bandyopadhyay, Jong Bae Seo, Revathy Sampath-Kumar, Jerrold M. Olefsky

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Insulin resistance is a major factor in obesity-linked type 2 diabetes. PPARγ is a master regulator of adipogenesis, and small molecule agonists, termed thiazolidinediones, are potent therapeutic insulin sensitizers. Here, we studied the role of transcriptional co-activator with PDZ-binding motif (TAZ) as a transcriptional co-repressor of PPARγ. We found that adipocyte-specific TAZ knockout (TAZ AKO) mice demonstrate a constitutively active PPARγ state. Obese TAZ AKO mice show improved glucose tolerance and insulin sensitivity compared to littermate controls. PPARγ response genes are upregulated in adipose tissue from TAZ AKO mice and adipose tissue inflammation was also decreased. In vitro and in vivo mechanistic studies revealed that the TAZ-PPARγ interaction is partially dependent on ERK-mediated Ser112 PPARγ phosphorylation. As adipocyte PPARγ Ser112 phosphorylation is increased in obesity, repression of PPARγ activity by TAZ could contribute to insulin resistance. These results identify TAZ as a new factor in the development of obesity-induced insulin resistance. El Ouarrat and Isaac et al. show that TAZ, a member of the Hippo pathway, functions as a PPARγ co-repressor in adipocytes. Adipocyte-specific TAZ KO increases PPARγ activity, reduces adipose inflammation, and improves insulin sensitivity and glucose tolerance in obese mice.

Original languageEnglish (US)
Pages (from-to)162-173.e5
JournalCell Metabolism
Volume31
Issue number1
DOIs
StatePublished - Jan 7 2020

Keywords

  • Hippo pathway
  • PPAR gamma
  • TAZ
  • adipocyte
  • glucose tolerance
  • insulin sensitivity
  • obesity
  • transcriptional co-activator with PDZ-binding motif

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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