TY - JOUR
T1 - Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity
AU - Li, Pingping
AU - Fan, Wuqiang
AU - Xu, Jianfeng
AU - Lu, Min
AU - Yamamoto, Hiroyasu
AU - Auwerx, Johan
AU - Sears, Dorothy D.
AU - Talukdar, Saswata
AU - Oh, Dayoung
AU - Chen, Ai
AU - Bandyopadhyay, Gautam
AU - Scadeng, Miriam
AU - Ofrecio, Jachelle M.
AU - Nalbandian, Sarah
AU - Olefsky, Jerrold M.
N1 - Funding Information:
We thank Elizabeth J. Hansen for editorial assistance; the Flow Cytometry Resource (Dennis Young) for FACS analysis at the Rebecca and John Moores Cancer Center; and we thank the UCSD Histology Core lab for technical help with processing tissue specimens and microscope analysis. This study was funded in part by the National Institutes of Health grants NIDDK DK033651 (J.M.O.), DK063491 (J.M.O.), DK 074868 (J.M.O.), DK059820 (J.A.), and EU Ideas program (ERC-2008-AdG-23118), the Swiss National Science Foundation, and the Eunice Kennedy Shriver NICHD/NIH through a cooperative agreement U54 HD 012303-25 as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research.
PY - 2011/11/11
Y1 - 2011/11/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2011.09.050
DO - 10.1016/j.cell.2011.09.050
M3 - Article
C2 - 22078880
AN - SCOPUS:81055144760
SN - 0092-8674
VL - 147
SP - 815
EP - 826
JO - Cell
JF - Cell
IS - 4
ER -