Role of glucose-dependent insulinotropic polypeptide in adipose tissue inflammation of dipeptidylpeptidase 4-deficient rats

Authors

  • Shani Ben-Shlomo,

    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Isabel Zvibel,

    Corresponding author
    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Chen Varol,

    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Lior Spektor,

    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Amir Shlomai,

    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Erwin M. Santo,

    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Zamir Halpern,

    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Ran Oren,

    1. Gastroenterology Institute, Hadassah Medical Center, Jerusalem, Israel
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  • Sigal Fishman

    1. The Research Center for Digestive Tract and Liver Diseases, The Department of Gastroenterology and Liver diseases, Tel-Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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  • Disclosure: The authors declare that there is no duality of interest associated with this manuscript.

  • Author contributions: SBS, IZ, SF, LS and CV contributed to the experimental design, data collection, analysis and manuscript preparation. SBS, IZ, SF, LS, CV, AS, EMS, ZH, RO contributed to the manuscript preparation, data analysis and intellectual input. All the authors have approved the final version of the article.

  • Funding agencies: The studies were supported by a grant from the Israeli Society for the Study of Liver Disease to S.F.

Abstract

Objectives

Dipeptidyl peptidase 4 (DPP4) inhibitors, used in obese diabetic patients, reduce inflammation in several models. The role of chronic DPP4-deficiency (DPP4-) in diet-induced obesity with respect to insulin sensitivity and adipose tissue inflammation was investigated.

Design and Methods

Insulin resistance was induced by 2 months high fat diet (HFD). In vitro effects of glucose-dependent insulinotropic polypeptide (GIP) were assessed in adipose tissue explants and stromal vascular fraction (SVF).

Results

HFD-fed DPP4-rats gained significantly more weight and visceral fat mass, yet were more insulin sensitive. Adipose tissue of DPP4- rats demonstrated increased adipocyte maturation and increased expression of enzymes involved in triglyceride uptake and synthesis, yet increased adiponectin mRNA, reduced mRNA of proinflammatory cytokines and reduced vascular adhesion molecules, suggesting reduced inflammation. In vitro and in vivo experiments explored the role of GIP in inducing this phenotype. Indeed, we demonstrated that GIP directly enhanced adiponectin expression in rat and human adipose tissue explants and in SVF. Lastly, GIP administration to normal or HFD-fed rats elevated serum adiponectin and improved their glucose tolerance test.

Conclusion

In a HFD model, DPP4-rats exhibited reduced adipose tissue inflammation and improved insulin resistance, which may be mediated in part by GIP induction of adiponectin.

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