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

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          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.

          Abstract

          During obesity, chronic inflammation leads to insulin resistance and diabetes. Here, Brenachot et al. show that Protein Tyrosine Phosphatase Receptor Gamma is upregulated in obesity by inflammatory signals and correlates with insulin resistance in humans. Its deletion in mouse models of obesity and inflammation ameliorates insulin resistance by suppressing glucose production.

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          Most cited references 28

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          IKK-beta links inflammation to obesity-induced insulin resistance.

          Inflammation may underlie the metabolic disorders of insulin resistance and type 2 diabetes. IkappaB kinase beta (IKK-beta, encoded by Ikbkb) is a central coordinator of inflammatory responses through activation of NF-kappaB. To understand the role of IKK-beta in insulin resistance, we used mice lacking this enzyme in hepatocytes (Ikbkb(Deltahep)) or myeloid cells (Ikbkb(Deltamye)). Ikbkb(Deltahep) mice retain liver insulin responsiveness, but develop insulin resistance in muscle and fat in response to high fat diet, obesity or aging. In contrast, Ikbkb(Deltamye) mice retain global insulin sensitivity and are protected from insulin resistance. Thus, IKK-beta acts locally in liver and systemically in myeloid cells, where NF-kappaB activation induces inflammatory mediators that cause insulin resistance. These findings demonstrate the importance of liver cell IKK-beta in hepatic insulin resistance and the central role of myeloid cells in development of systemic insulin resistance. We suggest that inhibition of IKK-beta, especially in myeloid cells, may be used to treat insulin resistance.
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            IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.

            Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.
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              Integrative genomic approaches identify IKBKE as a breast cancer oncogene.

              The karyotypic chaos exhibited by human epithelial cancers complicates efforts to identify mutations critical for malignant transformation. Here we integrate complementary genomic approaches to identify human oncogenes. We show that activation of the ERK and phosphatidylinositol 3-kinase (PI3K) signaling pathways cooperate to transform human cells. Using a library of activated kinases, we identify several kinases that replace PI3K signaling and render cells tumorigenic. Whole genome structural analyses reveal that one of these kinases, IKBKE (IKKepsilon), is amplified and overexpressed in breast cancer cell lines and patient-derived tumors. Suppression of IKKepsilon expression in breast cancer cell lines that harbor IKBKE amplifications induces cell death. IKKepsilon activates the nuclear factor-kappaB (NF-kappaB) pathway in both cell lines and breast cancers. These observations suggest a mechanism for NF-kappaB activation in breast cancer, implicate the NF-kappaB pathway as a downstream mediator of PI3K, and provide a framework for integrated genomic approaches in oncogene discovery.
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                Author and article information

                Contributors
                giorgio.ramadori@unige.ch
                roberto.coppari@unige.ch
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                28 November 2017
                28 November 2017
                2017
                : 8
                Affiliations
                [1 ]ISNI 0000 0001 2322 4988, GRID grid.8591.5, Department of Cell Physiology and Metabolism, , Faculty of Medicine, University of Geneva, ; 1211 Geneva 4, Switzerland
                [2 ]ISNI 0000 0001 2322 4988, GRID grid.8591.5, Diabetes Center of the Faculty of Medicine, , University of Geneva, ; 1211 Geneva 4, Switzerland
                [3 ]ISNI 0000 0001 2322 4988, GRID grid.8591.5, Laboratory of Metabolism, Department of Internal Medicine Specialties, , Faculty of Medicine, University of Geneva, ; 1211 Geneva, Switzerland
                [4 ]ISNI 0000 0000 9269 4097, GRID grid.256642.1, Advanced Scientific Research Leaders Development Unit, , Gunma University, ; 3-39-15 Showa-machi, Maebashi, Gunma 371-8512 Japan
                [5 ]ISNI 0000 0000 9269 4097, GRID grid.256642.1, Metabolic Signal Research Center, , Institute for Molecular and Cellular Regulation, Gunma University, ; 3-39-15 Showa-machi, Maebashi, Gunma 371-8512 Japan
                [6 ]ISNI 0000 0001 0721 9812, GRID grid.150338.c, Clinical Pathology, , Geneva University Hospitals, Rue Gabrielle Perret-Gentil, ; 1211 Geneva 14, Switzerland
                [7 ]ISNI 0000 0001 0721 9812, GRID grid.150338.c, Gastroenterology and Hepatology, , Geneva University Hospitals, Rue Gabrielle Perret-Gentil, ; 1211 Geneva 14, Switzerland
                [8 ]ISNI 0000 0001 2109 4251, GRID grid.240324.3, Department of Psychiatry, , New York University Langone School of Medicine, ; New York, NY 10016 USA
                [9 ]ISNI 0000 0001 2353 6535, GRID grid.428999.7, Department of Neuroscience, Institut Pasteur, ; 75824 Paris, France
                Article
                2074
                10.1038/s41467-017-02074-2
                5703876
                29180649
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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