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The polyunsaturated nature of n-3 fatty acids makes them prone to oxidative damage. However, it is not clear if n-3 fatty acids are simply a passive site for oxidative attack or if they also modulate mitochondrial reactive oxygen species (ROS) production. The present study used fat-1 transgenic mice, that are capable of synthesizing n-3 fatty acids, to investigate the influence of increases in n-3 fatty acids and resultant decreases in the n-6:n-3 ratio on liver mitochondrial H(2)O(2) production and electron transport chain (ETC) activity. There was an increase in n-3 fatty acids and a decrease in the n-6:n-3 ratio in liver mitochondria from the fat-1 compared to control mice. This change was largely due to alterations in the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine, with only a small percentage of fatty acids in cardiolipin being altered in the fat-1 animals. The lipid changes in the fat-1 mice were associated with a decrease (p

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 ?3 fatty acids. Remarkably the increased ?3 fatty acid levels primarily inhibit NF ?B dependent inflammatory responses by uncoupling NF ?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. © 2013 Elsevier Inc.