Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity

M Spite, J Hellmann, Y Tang, SP Mathis… - The Journal of …, 2011 - journals.aai.org
M Spite, J Hellmann, Y Tang, SP Mathis, M Kosuri, A Bhatnagar, VR Jala, B Haribabu
The Journal of Immunology, 2011journals.aai.org
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 …
Abstract
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 (ie, 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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