title: Antigen Presentation and T-Cell Activation Are Critical for RBP4-Induced Insulin Resistance.
abstract: Adipose tissue (AT) inflammation contributes to impaired insulin action, which is a major cause of type 2 diabetes. RBP4 is an adipocyte- and liver-derived protein with an important role in insulin resistance, metabolic syndrome, and AT inflammation. RBP4 elevation causes AT inflammation by activating innate immunity, which elicits an adaptive immune response. RBP4-overexpressing mice (RBP4-Ox) are insulin resistant and glucose intolerant and have increased AT macrophages and T-helper 1 cells. We show that high-fat diet-fed RBP4(-/-) mice have reduced AT inflammation and improved insulin sensitivity versus wild type. We also elucidate the mechanism for RBP4-induced macrophage antigen presentation and subsequent T-cell activation. In RBP4-Ox, AT macrophages display enhanced c-Jun N-terminal kinase, extracellular signal-related kinase, and p38 phosphorylation. Inhibition of these pathways and of NF-κB reduces activation of macrophages and CD4 T cells. MyD88 is an adaptor protein involved in proinflammatory signaling. In macrophages from MyD88(-/-) mice, RBP4 fails to stimulate secretion of tumor necrosis factor, IL-12, and IL-6 and CD4 T-cell activation. In vivo blockade of antigen presentation by treating RBP4-Ox mice with CTLA4-Ig, which blocks costimulation of T cells, is sufficient to reduce AT inflammation and improve insulin resistance. Thus, MyD88 and downstream mitogen-activated protein kinase and NF-κB pathways are necessary for RBP4-induced macrophage antigen presentation and subsequent T-cell activation. Also, blocking antigen presentation with CTLA4-Ig improves RBP4-induced insulin resistance and macrophage-induced T-cell activation.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Moraes-Vieira
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Angela
authors.initials: A
authors.lastname: Castoldi
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Pratik
authors.initials: P
authors.lastname: Aryal
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Wellenstein
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Odile D
authors.initials: OD
authors.lastname: Peroni
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA bkahn@bidmc.harvard.edu.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D056704:Adaptive Immunity; D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D059305:Diet, High-Fat / Q000009:adverse effects; D018149:Glucose Intolerance / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D007333:Insulin Resistance; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma