Adipocyte NCoR knockout decreases PPAR? phosphorylation and enhances PPAR? activity and insulin sensitivity.

ABSTRACT: Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPAR? response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPAR? ser-273 phosphorylation was reduced, creating a constitutively active PPAR? state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPAR?. The dominant function of adipocyte NCoR is to transrepress PPAR? and promote PPAR? ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.

SUBMITTER: Li P 

PROVIDER: S-EPMC3783197 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature