期刊
CELL
卷 155, 期 1, 页码 200-214出版社
CELL PRESS
DOI: 10.1016/j.cell.2013.08.054
关键词
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资金
- Ecole Polytechnique Federale de Lausanne
- Swiss National Science Foundation
- EU Ideas program [ERC-AdG-23118]
- Eunice Kennedy Shriver NICHD/NIH through a Cooperative Centers Program in Reproduction and Infertility Research
- [DK033651]
- [DK074868]
- [DK-063491]
- [DK-09062]
- [GM069338]
- [DK091183]
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 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.
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