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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.

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