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

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

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85 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)200-214
Number of pages15
JournalCell
Volume155
Issue number1
DOIs
StatePublished - Sep 26 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Li, P., Spann, N. J., Kaikkonen, M. U., Lu, M., Oh, D., Fox, J. N., Bandyopadhyay, G., Talukdar, S., Xu, J., Lagakos, W. S., Patsouris, D., Armando, A., Quehenberger, O., Dennis, E. A., Watkins, S. M., Auwerx, J., Glass, C. K., & Olefsky, J. M. (2013). NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids. Cell, 155(1), 200-214. https://doi.org/10.1016/j.cell.2013.08.054