Skip to main content
eScholarship
Open Access Publications from the University of California

UC San Diego

UC San Diego Previously Published Works bannerUC San Diego

NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids.

  • Author(s): 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
  • et al.
Abstract

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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View