Long-acting glucose-dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation

Chen Varol, Isabel Zvibel, Lior Spektor, Fernanda Dana Mantelmacher, Milena Vugman, Tamar Thurm, Marian Khatib, Elinor Elmaliah, Zamir Halpern, Sigal Fishman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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-Ala2]GIP. Administration of [d-Ala2]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 Ly6Chi monocytes and F4/80hi CD11c+ macrophages, associated with IR. In addition, [d-Ala2]GIP reduced adipose tissue infiltration of IFN-γ-producing CD8+ and CD4+ T cells. Furthermore, [d-Ala2]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-Ala2]GIP also reduced the numbers of circulating neutrophils and proinflammatory Ly6Chi 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.

Original languageEnglish
Pages (from-to)4002-4009
Number of pages8
JournalJournal of Immunology
Volume193
Issue number8
DOIs
StatePublished - 15 Oct 2014

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