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Chronic inflammation is a key component of obesity–induced insulin resistance and plays a central role in metabolic disease. In this study, we found that the major insulin target tissues, liver, muscle and adipose tissue exhibit increased levels of the chemotactic eicosanoid LTB4 in obese high fat diet (HFD) mice compared to lean chow fed mice. Inhibition of the LTB4 receptor, Ltb4r1, through either genetic or pharmacologic loss of function results in an anti–inflammatory phenotype with protection from systemic insulin resistance and hepatic steatosis in the setting of both HFD–induced and genetic obesity. Importantly, in vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways in macrophages, promoted de novo hepatic lipogenesis, decreased insulin stimulated glucose uptake in L6 myocytes, increased gluconeogenesis, and impaired insulin–mediated suppression of hepatic glucose output (HGO) in primary mouse hepatocytes. This was accompanied by decreased insulin stimulated Akt phosphorylation and increased Irs1 and Irs2 serine phosphorylation and all of these events were Gαi and Jnk dependent. Taken together, these observations elucidate a novel role of LTB4/Ltb4r1 in the etiology of insulin resistance in hepatocytes and myocytes, and shows that in vivo inhibition of Ltb4r1 leads to robust insulin sensitizing effects.

Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The co-repressor 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 de-repression 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 pro-inflammatory 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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Summary Here, we demonstrate that the fractalkine(FKN)/CX3CR1 system represents a previously undescribed regulatory mechanism for pancreatic islet beta cell function and insulin secretion. CX3CR1 KO mice exhibited a marked defect in glucose and GLP1-stimulated insulin secretion, and this defect was also observed in vitro in isolated islets from CX3CR1 KO mice. In vivo administration of FKN improved glucose tolerance with an increase in insulin secretion. In vitro treatment of islets with FKN increased intracellular Ca2+ and potentiated insulin secretion in both mouse and human islets. The KO islets exhibited reduced expression of a set of genes necessary for the fully functional, differentiated beta cell state, whereas, treatment of WT islets with FKN led to increased expression of these genes. Lastly, expression of FKN in islets was decreased by aging and HFD/obesity, suggesting that decreased fractalkine/CX3CR1 signaling could be a mechanism underlying beta cell dysfunction in type 2 diabetes.