- Main
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.
Published Web Location
https://doi.org/10.1016/j.cell.2013.08.054Abstract
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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