Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity

Pingping Li, Wuqiang Fan, Jianfeng Xu, Min Lu, Hiroyasu Yamamoto, Johan Auwerx, Dorothy D. Sears, Saswata Talukdar, Dayoung Oh, Ai Chen, Gautam Bandyopadhyay, Miriam Scadeng, Jachelle M. Ofrecio, Sarah Nalbandian, Jerrold M. Olefsky

Research output: Contribution to journalArticle

185 Scopus citations

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. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.

Original languageEnglish (US)
Pages (from-to)815-826
Number of pages12
JournalCell
Volume147
Issue number4
DOIs
StatePublished - Nov 11 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Li, P., Fan, W., Xu, J., Lu, M., Yamamoto, H., Auwerx, J., Sears, D. D., Talukdar, S., Oh, D., Chen, A., Bandyopadhyay, G., Scadeng, M., Ofrecio, J. M., Nalbandian, S., & Olefsky, J. M. (2011). Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell, 147(4), 815-826. https://doi.org/10.1016/j.cell.2011.09.050