title: Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity.
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 (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.
authors: Division of Cardiovascular Medicine, Diabetes and Obesity Center, University of Louisville School of Medicine, Louisville, KY 40202, USA. Matthew.spite@louisville.edu
authors: Matthew
authors: M
authors: Spite
authors: Jason
authors: J
authors: Hellmann
authors: Yunan
authors: Y
authors: Tang
authors: Steven P
authors: SP
authors: Mathis
authors: Madhavi
authors: M
authors: Kosuri
authors: Aruni
authors: A
authors: Bhatnagar
authors: Venkatakrishna R
authors: VR
authors: Jala
authors: Bodduluri
authors: B
authors: Haribabu
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D007333:Insulin Resistance / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D015850:Interleukin-6; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4