Deficiency of the leukotriene B4 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: 5.36). 08/2011; 187(4):1942-9. DOI: 10.4049/jimmunol.1100196
Source: PubMed

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.

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    Ribeiro Luciano, Filgueiras, Stephanie L Brandt, Soujuan Wang, Zhuo Wang, David L Morris, Carmella Evans-Molina, Raghavendra G Mirmira, Sonia Jancar, C Henrique Serezani
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    ABSTRACT: Type 1 diabetes mellitus (T1DM) is associated with chronic systemic inflammation and enhanced sus-ceptibility to systemic bacterial infection (sepsis). We hypothesized that low insulin concentrations in T1DM trigger the enzyme 5-lipoxygenase (5-LO) to produce the lipid mediator leukotriene B 4 (LTB 4), which triggers systemic inflammation that may increase susceptibility to polymicrobial sepsis. Consistent with chronic inflammation, peritoneal macrophages from two mouse models of T1DM had greater abundance of the adaptor MyD88 (myeloid differentiation factor 88) and its direct transcriptional effector STAT-1 (signal transducer and activator of transcription 1) than macrophages from nondiabetic mice. Expression of Alox5, which encodes 5-LO, and the concentration of the proinflammatory cytokine interleukin-1b (IL-1b) were also increased in peritoneal macrophages and serum from T1DM mice. Insulin treatment reduced LTB 4 concentrations in the circulation and Myd88 and Stat1 expression in the macro-phages from T1DM mice. T1DM mice treated with a 5-LO inhibitor had reduced Myd88 mRNA in macro-phages and increased abundance of IL-1 receptor antagonist and reduced production of IL-b in the circulation. T1DM mice lacking 5-LO or the receptor for LTB 4 also produced less proinflammatory cyto-kines. Compared to wild-type or untreated diabetic mice, T1DM mice lacking the receptor for LTB 4 or treated with a 5-LO inhibitor survived polymicrobial sepsis, had reduced production of proinflammatory cytokines, and had decreased bacterial counts. These results uncover a role for LTB 4 in promoting sterile inflammation in diabetes and the enhanced susceptibility to sepsis in T1DM.
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    ABSTRACT: Adipose tissue metabolism is a critical regulator of adiposity and whole-body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study is to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower VO2, VCO2 and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in HF-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50% and responses to FCCP were increased in WAT from mice fed a HFD. Moreover, Pgc1a was downregulated and Cox7a1 was upregulated after 6 weeks of HFD. After 12 weeks of HFD, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity.
    AJP Endocrinology and Metabolism 06/2014; · 4.09 Impact Factor
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    ABSTRACT: Obesity is a major risk factor for insulin resistance and type-2 diabetes. A chronic low grade inflammatory state has been described during obesity and associated with insulin resistance pathogenesis. Results from animal studies are in favor of a role of the leukotriene (LT) pathway in obesity induced-insulin resistance. However, there is a paucity of data regarding this association in human obesity. Therefore, the aim of this study was to investigate whether LT production was associated with insulin resistance and other metabolic parameters in a cohort of obese subjects. Forty-six (70% females) obese subjects (BMI≧30 kg/m2) without known diabetes and without inflammatory disease (CRP<10 mg/l) were included. Median age was 44 years (16-80) with a median BMI of 36.8 kg/m2 (30-51). Insulin resistance was evaluated by HOMA-IR index and glucose tolerance test. Urinary LTE4 (U-LTE4) concentration was measured by enzyme immune assay. Screening for obstructive sleep apnea was performed. There was a positive association of U-LTE4 with waist to hip ratio, systolic blood pressure and HOMA-IR in univariate analysis. Further, waist to hip ratio remained the only parameter significantly correlated with U-LTE4, in adjusted multivariate analysis. Taken together, these results confirm the previously established notion of chronic low grade inflammation in obesity and further suggests a role for the LT pathway in obesity-associated development of insulin resistance in humans.
    PLoS ONE 12/2014; 9(12):e104593. · 3.53 Impact Factor


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May 21, 2014