- Li, Pingping;
- Spann, Nathanael J;
- Kaikkonen, Minna U;
- Lu, Min;
- Oh, Da Young;
- Fox, Jesse N;
- Bandyopadhyay, Gautam;
- Talukdar, Saswata;
- Xu, Jianfeng;
- Lagakos, William S;
- Patsouris, David;
- Armando, Aaron;
- Quehenberger, Oswald;
- Dennis, Edward A;
- Watkins, Steven M;
- Auwerx, Johan;
- Glass, Christopher K;
- Olefsky, Jerrold M
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 derepression 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 proinflammatory 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.