title: RBP4 activates antigen-presenting cells, leading to adipose tissue inflammation and systemic insulin resistance.
abstract: Insulin resistance is a major cause of diabetes and is highly associated with adipose tissue (AT) inflammation in obesity. RBP4, a retinol transporter, is elevated in insulin resistance and contributes to increased diabetes risk. We aimed to determine the mechanisms for RBP4-induced insulin resistance. Here we show that RBP4 elevation causes AT inflammation by activating innate immunity that elicits an adaptive immune response. RBP4-overexpressing mice (RBP4-Ox) are insulin resistant and glucose intolerant and have increased AT macrophage and CD4 T cell infiltration. In RBP4-Ox, AT CD206(+) macrophages express proinflammatory markers and activate CD4 T cells while maintaining alternatively activated macrophage markers. These effects result from direct activation of AT antigen-presenting cells (APCs) by RBP4 through a JNK-dependent pathway. Transfer of RBP4-activated APCs into normal mice is sufficient to induce AT inflammation, insulin resistance, and glucose intolerance. Thus, RBP4 causes insulin resistance, at least partly, by activating AT APCs that induce CD4 T cell Th1 polarization and AT inflammation.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
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, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Yore
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Dwyer
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Ismail
authors.initials: I
authors.lastname: Syed
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
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, 330 Brookline Avenue, Boston, MA 02215, USA. Electronic address: bkahn@bidmc.harvard.edu.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D018149:Glucose Intolerance; D006801:Humans; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism; D059467:Transcriptome
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; C101326:RBP4 protein, human; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D054839:Retinol-Binding Proteins, Plasma; D048031:JNK Mitogen-Activated Protein Kinases