title: LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes.
abstract: Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)-fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4-Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: William S
authors.initials: WS
authors.lastname: Lagakos
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Olivia
authors.initials: O
authors.lastname: Osborn
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Chung
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Michael
authors.initials: M
authors.lastname: Maris
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Jachelle M
authors.initials: JM
authors.lastname: Ofrecio
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Taguchi
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000276:immunology / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology*; D007975:Leukotriene B4 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008820:Mice, Obese; D018485:Muscle Fibers, Skeletal / Q000276:immunology* / Q000378:metabolism; D009765:Obesity / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D051057:Proto-Oncogene Proteins c-akt