E-GEOD-50944 - NCoR Repression of LXRs Restricts Macrophage Biosynthesis of Insulin-Sensitizing Omega 3 Fatty Acids
Released on 9 October 2013, last updated on 2 May 2014
Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that de-repression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for pro-inflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin sensitizing therapies. ChIP-Seq and Gro-Seq profiling was performed in thioglycollate-elicited peritoneal macrophages treated as indicated.
Nathanael Judge Spann <firstname.lastname@example.org>, Aaron Armando, Christopher K Glass, Da-Young Oh, David Patsouris, Edward A Dennis, Gautam Bandyopadhyay, Jerrold M Olefsky, Jesse N Fox, Jianfeng Xu, Johan Auwerx, Min Lu, Minna U Kaikkonen, Nathanael Spann, Oswald Quehenberger, Pingping Li, Saswata Talukdar, Steven M Watkins, William S Lagakos
NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Li P, Spann NJ, Kaikkonen MU, Lu M, Oh da Y, Fox JN, Bandyopadhyay G, Talukdar S, Xu J, Lagakos WS, Patsouris D, Armando A, Quehenberger O, Dennis EA, Watkins SM, Auwerx J, Glass CK, Olefsky JM. , Europe PMC 24074869