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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Available from: Jason Hellmann, Sep 30, 2015
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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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    Inflammation 05/2014; 37(4). DOI:10.1007/s10753-014-9914-1 · 2.21 Impact Factor
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    • "inflammatory liver injury, insulin resistance, and TNFa-induced hepatocyte cell death (Horrillo et al., 2010; Martínez-Clemente et al., 2010; Spite et al., 2011). Omega-3 fatty acid precursors and SPMs exert opposite roles in hepatic steatosis to those described for omega-6-derived eicosanoids. "
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    Cell metabolism 11/2013; 19(1). DOI:10.1016/j.cmet.2013.10.006 · 17.57 Impact Factor
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    • "In the latter contexts, the leukotriene pathway may not only serve as diagnostic markers but could potentially also offer mechanistic insights into the role of inflammation in metabolic disease. For example, targeting either leukotriene receptor signaling or leukotriene synthesis decreases proinflammatory cytokine secretion from visceral fat [5] and protects against insulin resistance in diet-induced obesity [6] [7]. "
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