Deficiency of the Leukotriene B-4 Receptor, BLT-1, Protects against Systemic Insulin Resistance in Diet-Induced Obesity

Division of Cardiovascular Medicine, Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2011; 187(4):1942-9. DOI: 10.4049/jimmunol.1100196
Source: PubMed


Chronic inflammation is an underlying factor linking obesity with insulin resistance. Diet-induced obesity promotes an increase in circulating levels of inflammatory monocytes and their infiltration into expanding adipose tissue. Nevertheless, the endogenous pathways that trigger and sustain chronic low-grade inflammation in obesity are incompletely understood. In this study, we report that a high-fat diet selectively increases the circulating levels of CD11b(+) monocytes in wild-type mice that express leukotriene B(4) receptor, BLT-1, and that this increase is abolished in BLT-1-null mice. The accumulation of classically activated (M1) adipose tissue macrophages (ATMs) and the expression of proinflammatory cytokines and chemokines (i.e., IL-6 and Ccl2) was largely blunted in adipose tissue of obese BLT-1(-/-) mice, whereas the ratio of alternatively activated (M2) ATMs to M1 ATMs was increased. Obese BLT-1(-/-) mice were protected from systemic glucose and insulin intolerance and this was associated with a decrease in inflammation in adipose tissue and liver and a decrease in hepatic triglyceride accumulation. Deletion of BLT-1 prevented high fat-induced loss of insulin signaling in liver and skeletal muscle. These observations elucidate a novel role of chemoattractant receptor, BLT-1, in promoting monocyte trafficking to adipose tissue and promoting chronic inflammation in obesity and could lead to the identification of new therapeutic targets for treating insulin resistance in obesity.

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    • "Obesity promotes the mobilization of monocytes from the bone marrow in part by activating the CCR2. Deficiency of CCR2 or its ligand, MCP-1, in mice results in failure of monocyte mobilization and is associated with protection from monocyte infiltration into adipose tissue and insulin resistance [70, 71]; Spite et al. [72] report that activation of the leukotriene B4 (LTB4) and its receptor BLT-1 axis is required for obesity-induced increases in peripheral blood monocytes and subsequent adipose tissue macrophage accumulation. "
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