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: Matthew Spite, Jason Hellmann, Yunan Tang, Steven P Mathis, Madhavi Kosuri, Aruni Bhatnagar, Venkatakrishna R Jala, Bodduluri Haribabu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 187 Issue 4 Pg. 1942-9 (Aug 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21742977 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CD11b Antigen
• Ccl2 protein, mouse
• Chemokine CCL2
• Dietary Fats
• Interleukin-6
• Ltb4r1 protein, mouse
• Receptors, Leukotriene B4

Topics

• Adipose Tissue (immunology, metabolism)
• Animals
• CD11b Antigen (immunology, metabolism)
• Cell Movement (genetics, immunology)
• Chemokine CCL2 (biosynthesis, genetics, immunology)
• Dietary Fats (adverse effects, pharmacology)
• Female
• Gene Deletion
• Inflammation (etiology, genetics, immunology, metabolism, therapy)
• Insulin Resistance (genetics, immunology)
• Interleukin-6 (biosynthesis, genetics, immunology)
• Liver (immunology, metabolism)
• Macrophage Activation (genetics, immunology)
• Macrophages (immunology, metabolism)
• Male
• Mice
• Mice, Knockout
• Monocytes (immunology, metabolism)
• Muscle, Skeletal (immunology, metabolism)
• Obesity (etiology, genetics, immunology, metabolism)
• Receptors, Leukotriene B4 (genetics, immunology, metabolism)