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Nat Commun. 2017 Nov 28;8(1):1820. doi: 10.1038/s41467-017-02074-2.

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

Author information

1
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland.
2
Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland.
3
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland. giorgio.ramadori@unige.ch.
4
Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland. giorgio.ramadori@unige.ch.
5
Laboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland.
6
Advanced Scientific Research Leaders Development Unit, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512, Japan.
7
Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512, Japan.
8
Clinical Pathology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211, Geneva 14, Switzerland.
9
Gastroenterology and Hepatology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211, Geneva 14, Switzerland.
10
Department of Psychiatry, New York University Langone School of Medicine, New York, NY, 10016, USA.
11
Department of Neuroscience, Institut Pasteur, 75824, Paris, France.
12
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland. roberto.coppari@unige.ch.
13
Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland. roberto.coppari@unige.ch.

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.

PMID:
29180649
PMCID:
PMC5703876
DOI:
10.1038/s41467-017-02074-2
[Indexed for MEDLINE]
Free PMC Article

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