Li, PingpingSpann, Nathanael J.Kaikkonen, Minna U.Lu, MinOh, Da YoungFox, Jesse N.Bandyopadhyay, GautamTalukdar, SaswataXu, JianfengLagakos, William S.Patsouris, DavidArmando, AaronQuehenberger, OswaldDennis, Edward A.Watkins, Steven M.Auwerx, JohanGlass, Christopher K.Olefsky, Jerrold M.2013-11-042013-11-042013-11-04201310.1016/j.cell.2013.08.054https://infoscience.epfl.ch/handle/20.500.14299/96624WOS:000324916700020Macrophage-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 omega 3 fatty acids. Remarkably, the increased omega 3 fatty acid levels primarily inhibit NF-kappa B-dependent inflammatory responses by uncoupling NF-kappa B 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.text::journal::journal article::research article