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

165 Citations (Scopus)

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

Fingerprint

Co-Repressor Proteins
Peroxisome Proliferator-Activated Receptors
Phosphorylation
Adipocytes
Insulin Resistance
Insulin
Tissue
Adipose Tissue
Inflammation
Obesity
Glucose
Adipogenesis
Macrophages
Clamping devices
Medical problems
Infiltration
Knockout Mice
Liver
Type 2 Diabetes Mellitus
Muscle

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Li, P., Fan, W., Xu, J., Lu, M., Yamamoto, H., Auwerx, J., ... 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

Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. / Li, Pingping; Fan, Wuqiang; Xu, Jianfeng; Lu, Min; Yamamoto, Hiroyasu; Auwerx, Johan; Sears, Dorothy D.; Talukdar, Saswata; Oh, Dayoung; Chen, Ai; Bandyopadhyay, Gautam; Scadeng, Miriam; Ofrecio, Jachelle M.; Nalbandian, Sarah; Olefsky, Jerrold M.

In: Cell, Vol. 147, No. 4, 11.11.2011, p. 815-826.

Research output: Contribution to journalArticle

Li, P, Fan, W, Xu, J, Lu, M, Yamamoto, H, Auwerx, J, Sears, DD, Talukdar, S, Oh, D, Chen, A, Bandyopadhyay, G, Scadeng, M, Ofrecio, JM, Nalbandian, S & Olefsky, JM 2011, 'Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity', Cell, vol. 147, no. 4, pp. 815-826. https://doi.org/10.1016/j.cell.2011.09.050
Li, Pingping ; Fan, Wuqiang ; Xu, Jianfeng ; Lu, Min ; Yamamoto, Hiroyasu ; Auwerx, Johan ; Sears, Dorothy D. ; Talukdar, Saswata ; Oh, Dayoung ; Chen, Ai ; Bandyopadhyay, Gautam ; Scadeng, Miriam ; Ofrecio, Jachelle M. ; Nalbandian, Sarah ; Olefsky, Jerrold M. / Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. In: Cell. 2011 ; Vol. 147, No. 4. pp. 815-826.
@article{357baa68e4b34201829bd4383bd952bf,
title = "Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ 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. 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.",
author = "Pingping Li and Wuqiang Fan and Jianfeng Xu and Min Lu and Hiroyasu Yamamoto and Johan Auwerx and Sears, {Dorothy D.} and Saswata Talukdar and Dayoung Oh and Ai Chen and Gautam Bandyopadhyay and Miriam Scadeng and Ofrecio, {Jachelle M.} and Sarah Nalbandian and Olefsky, {Jerrold M.}",
year = "2011",
month = "11",
day = "11",
doi = "10.1016/j.cell.2011.09.050",
language = "English (US)",
volume = "147",
pages = "815--826",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=81055144760&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81055144760&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2011.09.050

DO - 10.1016/j.cell.2011.09.050

M3 - Article

VL - 147

SP - 815

EP - 826

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

ER -