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Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance

Author

Listed:
  • Xavier Brenachot

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Giorgio Ramadori

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Rafael M. Ioris

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Christelle Veyrat-Durebex

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Jordi Altirriba

    (University of Geneva
    Faculty of Medicine, University of Geneva)

  • Ebru Aras

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Sanda Ljubicic

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Daisuke Kohno

    (Gunma University
    Institute for Molecular and Cellular Regulation, Gunma University)

  • Salvatore Fabbiano

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Sophie Clement

    (Geneva University Hospitals, Rue Gabrielle Perret-Gentil)

  • Nicolas Goossens

    (Geneva University Hospitals, Rue Gabrielle Perret-Gentil)

  • Mirko Trajkovski

    (Faculty of Medicine, University of Geneva
    University of Geneva)

  • Sheila Harroch

    (New York University Langone School of Medicine
    Department of Neuroscience, Institut Pasteur)

  • Francesco Negro

    (University of Geneva
    Geneva University Hospitals, Rue Gabrielle Perret-Gentil
    Geneva University Hospitals, Rue Gabrielle Perret-Gentil)

  • Roberto Coppari

    (Faculty of Medicine, University of Geneva
    University of Geneva)

Abstract

Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. Here, we show that hepatic expression of Protein Tyrosine Phosphatase Receptor Gamma (PTPR-γ) is stimulated by inflammation in obese/T2DM mice and positively correlates with indices of inflammation and insulin resistance in humans. NF-κB binds to the promoter of Ptprg and is required for inflammation-induced PTPR-γ expression. PTPR-γ loss-of-function lowers glycemia and insulinemia by enhancing insulin-stimulated suppression of endogenous glucose production. These phenotypes are rescued by re-expression of Ptprg only in liver of mice lacking Ptprg globally. Hepatic PTPR-γ overexpression that mimics levels found in obesity is sufficient to cause severe hepatic and systemic insulin resistance. We propose hepatic PTPR-γ as a link between obesity-induced inflammation and insulin resistance and as potential target for treatment of T2DM.

Suggested Citation

  • Xavier Brenachot & Giorgio Ramadori & Rafael M. Ioris & Christelle Veyrat-Durebex & Jordi Altirriba & Ebru Aras & Sanda Ljubicic & Daisuke Kohno & Salvatore Fabbiano & Sophie Clement & Nicolas Goossen, 2017. "Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02074-2
    DOI: 10.1038/s41467-017-02074-2
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    Cited by:

    1. Gloria Ursino & Giorgio Ramadori & Anna Höfler & Soline Odouard & Pryscila D. S. Teixeira & Florian Visentin & Christelle Veyrat-Durebex & Giulia Lucibello & Raquel Firnkes & Serena Ricci & Claudia R., 2022. "Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Eduardo H. Gilglioni & Ao Li & Wadsen St-Pierre-Wijckmans & Tzu-Keng Shen & Israel Pérez-Chávez & Garnik Hovhannisyan & Michela Lisjak & Javier Negueruela & Valerie Vandenbempt & Julia Bauzá-Martinez , 2024. "PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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