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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Fan
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Dorothy D
authors.initials: DD
authors.lastname: Sears
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.forename: DaYoung
authors.initials: D
authors.lastname: Oh
authors.forename: Ai
authors.initials: A
authors.lastname: Chen
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: Miriam
authors.initials: M
authors.lastname: Scadeng
authors.forename: Jachelle M
authors.initials: JM
authors.lastname: Ofrecio
authors.forename: Sarah
authors.initials: S
authors.lastname: Nalbandian
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D056970:Co-Repressor Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D045162:Thiazolidinediones
chemical_list: D056970:Co-Repressor Proteins; C539128:Ncor1 protein, mouse; D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma; D045162:Thiazolidinediones
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