title: Long-acting glucose-dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation.
abstract: Obesity induces low-grade chronic inflammation, manifested by proinflammatory polarization of adipose tissue innate and adaptive resident and recruited immune cells that contribute to insulin resistance (IR). The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that mediates postprandial insulin secretion and has anabolic effects on the adipose tissue. Importantly, recent evidence suggested that GIP is a potential suppressor of inflammation in several metabolic models. In this study, we aimed to investigate the immunoregulatory role of GIP in a murine model of diet-induced obesity (DIO) using the long-acting GIP analog [d-Ala(2)]GIP. Administration of [d-Ala(2)]GIP resulted in adipocytes of increased size, increased levels of adipose tissue lipid droplet proteins, indicating better lipid storage capacity, and reduced adipose tissue inflammation. Flow cytometry analysis revealed reduced numbers of inflammatory Ly6C(hi) monocytes and F4/80(hi)CD11c(+) macrophages, associated with IR. In addition, [d-Ala(2)]GIP reduced adipose tissue infiltration of IFN-γ-producing CD8(+) and CD4(+) T cells. Furthermore, [d-Ala(2)]GIP treatment induced a favorable adipose tissue adipokine profile, manifested by a prominent reduction in key inflammatory cytokines (TNF-α, IL-1β, IFN-γ) and chemokines (CCL2, CCL8, and CCL5) and an increase in adiponectin. Notably, [d-Ala(2)]GIP also reduced the numbers of circulating neutrophils and proinflammatory Ly6C(hi) monocytes in mice fed regular chow or a high-fat diet. Finally, the beneficial immune-associated effects were accompanied by amelioration of IR and improved insulin signaling in liver and adipose tissue. Collectively, our results describe key beneficial immunoregulatory properties for GIP in DIO and reveal that its augmentation ameliorates adipose tissue inflammation and improves IR.
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Chen
authors.initials: C
authors.lastname: Varol
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zvibel
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Lior
authors.initials: L
authors.lastname: Spektor
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Fernanda Dana
authors.initials: FD
authors.lastname: Mantelmacher
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Milena
authors.initials: M
authors.lastname: Vugman
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Tamar
authors.initials: T
authors.lastname: Thurm
authors.affiliation: Surgery Department, Tel-Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
authors.forename: Marian
authors.initials: M
authors.lastname: Khatib
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Elinor
authors.initials: E
authors.lastname: Elmaliah
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and.
authors.forename: Zamir
authors.initials: Z
authors.lastname: Halpern
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 64239, Israel; and sigalf@tlvmc.gov.il.
authors.forename: Sigal
authors.initials: S
authors.lastname: Fishman
mesh_terms: D017667:Adipocytes / Q000473:pathology; D052242:Adiponectin / Q000096:biosynthesis; D000273:Adipose Tissue / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D001786:Blood Glucose; D039521:CD11c Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054412:Chemokine CCL8 / Q000096:biosynthesis; D059305:Diet, High-Fat; D005749:Gastric Inhibitory Polypeptide / Q000627:therapeutic use*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology*; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D066292:Lipid Droplets / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D009765:Obesity / Q000188:drug therapy* / Q000473:pathology; D011964:Receptors, Gastrointestinal Hormone / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D052242:Adiponectin; D000943:Antigens, Differentiation; D000950:Antigens, Ly; D001786:Blood Glucose; D039521:CD11c Antigen; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; C515454:Ccl8 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054412:Chemokine CCL8; C587672:IL1B protein, mouse; D007328:Insulin; D053583:Interleukin-1beta; C494192:Ly-6C antigen, mouse; D011964:Receptors, Gastrointestinal Hormone; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; D005749:Gastric Inhibitory Polypeptide; D007371:Interferon-gamma; C041086:gastric inhibitory polypeptide receptor