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Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice

Nature Medicine volume 15, pages 940–945 (2009)Cite this article

Abstract

Although mast cell functions have classically been related to allergic responses1,2,3, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer4,5,6,7,8. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-γ (IFN-γ), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.

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Figure 1: Macrophages and mast cells in human WAT.
Figure 2: Mast cell deficiency and stabilization lowers diet-induced obesity and diabetes in male mice.
Figure 3: Mast cell functions in angiogenesis, apoptosis and protease expression.
Figure 4: Mast cell reconstitution in KitW-sh/W-sh mice.

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Acknowledgements

We thank S. Rizkalla and C. Poitou, who contributed to the clinical investigation program. We also thank B. Spiegelman and R.K. Gupta for their help with the 3T3-L1 culture. This study was supported partially by the Established Investigator Award from the American Heart Association (0840118N) (to G.-P.S.) and by US National Institutes of Health grants HL60942, HL67283, HL81090, HL88547 (G.-P.S.), HL34636 (P.L.), DK57521, DK56116 (B.B.K.) and DK52539 and DK64360 (G.S.H.). The clinical work was supported by the Programme Hospitalier de Recherche Clinique, Assistance Publique des Hôpitaux de Paris (AOR 02076), a grant from French National Agency of Research (RIOMA program N°ANR05-PCOD-030-02), and by the Commission of the European Communities (ADAPT project) (to K.C.).

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Authors and Affiliations

  1. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Jian Liu, Jiusong Sun, Jie Zhang, Jonathan N Glickman, Galina K Sukhova, Juan Du, Peter Libby, Richard S Blumberg & Guo-Ping Shi

  2. Institut National de la Santé et de la Recherche Médicale, U872, Nutriomique, Paris, France

    Adeline Divoux & Karine Clément

  3. University Pierre and Marie Curie-Paris 6, Cordeliers Research Center, Paris, France

    Karine Clément

  4. Nutrition Department, Assistance Publique-Hôpitaux de Paris, Pitié-Salpetrière Hospital, Paris, France

    Karine Clément

  5. Department of Medicine, University of California, San Francisco, California, USA

    Paul J Wolters

  6. Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, Massachusetts, USA

    Cem Z Gorgun & Gökhan S Hotamisligil

  7. Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA

    Alessandro Doria

  8. Department of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

    Barbara B Kahn

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Contributions

J.L. induced mouse obesity and diabetes, monitored body weight, performed insulin tolerance and glucose tolerance assays and completed all immunoblot analyses. A. Divoux performed human adipose tissue immunohistology. J.S. cultured mouse mast cells and performed mast cell reconstitution. J.Z. performed human serum tryptase ELISA. K.C. collected and provided all human serum samples and assisted with manuscript writing. J.N.G. helped with the mouse gastrointestinal tract tissue histology analysis. G.K.S. performed mouse tissue immunohistology. P.J.W. helped with data explanation and manuscript writing. J.D. helped with mouse tissue immunohistology. C.Z.G. performed mouse body tissue composition analysis. A. Doria performed human serum tryptase statistic analysis. P.L. assisted with the data interpretation and manuscript writing. R.S.B. helped with the gastrointestinal tract tissue histology analysis and assisted with the manuscript writing. B.B.K. assisted with the data interpretation and manuscript writing. G.S.H. helped with the body tissue composition data analysis. G.-P.S. designed the experiments, participated in all data analyses and prepared the manuscript.

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Correspondence to Guo-Ping Shi.

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Liu, J., Divoux, A., Sun, J. et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15, 940–945 (2009). https://doi.org/10.1038/nm.1994

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