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

Xavier Brenachot; Giorgio Ramadori; Rafael M Ioris; Christelle Veyrat-Durebex; Jordi Altirriba; Ebru Aras; Sanda Ljubicic; Daisuke Kohno; Salvatore Fabbiano; Sophie Clement; Nicolas Goossens; Mirko Trajkovski; Sheila Harroch; Francesco Negro; Roberto Coppari

doi:10.1038/s41467-017-02074-2

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

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

Authors

Xavier Brenachot^{1

2}, Giorgio Ramadori^{3

4}, Rafael M Ioris^{1

2}, Christelle Veyrat-Durebex^{1

2}, Jordi Altirriba^{2

5}, Ebru Aras^{1

2}, Sanda Ljubicic^{1

2}, Daisuke Kohno^{6

7}, Salvatore Fabbiano^{1

2}, Sophie Clement⁸, Nicolas Goossens⁹, Mirko Trajkovski^{1

2}, Sheila Harroch^{10

11}, Francesco Negro^{2

8

9}, Roberto Coppari^{12

13}

Affiliations

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. [email protected].
⁴ Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland. [email protected].
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. [email protected].
¹³ Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva 4, Switzerland. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Blood Glucose
Cell Line
Diabetes Mellitus, Type 2 / blood
Diabetes Mellitus, Type 2 / complications
Diabetes Mellitus, Type 2 / metabolism*
Female
Gene Expression
Gene Expression Profiling
Hep G2 Cells
Humans
Inflammation / metabolism
Insulin / blood
Insulin Resistance / physiology*
Interleukin-6 / metabolism
Lipid Metabolism
Lipopolysaccharides / adverse effects
Liver / drug effects
Liver / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Middle Aged
Models, Animal
NF-kappa B / metabolism
Obesity / blood
Obesity / complications
Obesity / metabolism*
Protein Tyrosine Phosphatases / metabolism
RNA, Messenger / biosynthesis
Receptor-Like Protein Tyrosine Phosphatases / genetics
Receptor-Like Protein Tyrosine Phosphatases / metabolism*
Sirtuin 1 / metabolism

Substances

Blood Glucose
Insulin
Interleukin-6
Lipopolysaccharides
NF-kappa B
RNA, Messenger
Protein Tyrosine Phosphatases
Receptor-Like Protein Tyrosine Phosphatases
Sirt1 protein, mouse
Sirtuin 1