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

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.

References

  1. 1

    Galli, S.J., Nakae, S. & Tsai, M. Mast cells in the development of adaptive immune responses. Nat. Immunol. 6, 135–142 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Bingham, C.O. III & Austen, K.F. Mast-cell responses in the development of asthma. J. Allergy Clin. Immunol. 105, S527–S534 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Robbie-Ryan, M. & Brown, M. The role of mast cells in allergy and autoimmunity. Curr. Opin. Immunol. 14, 728–733 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Secor, V.H., Secor, W.E., Gutekunst, C.A. & Brown, M.A. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 191, 813–822 (2000).

    CAS  Article  Google Scholar 

  5. 5

    Lee, D.M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Sun, J. et al. Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat. Med. 13, 719–724 (2007).

    CAS  Article  Google Scholar 

  7. 7

    Sun, J. et al. Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J. Clin. Invest. 117, 3359–3368 (2007).

    CAS  Article  Google Scholar 

  8. 8

    Coussens, L.M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    CAS  Article  Google Scholar 

  10. 10

    Rocha, V.Z. et al. Interferon-γ, a TH1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ. Res. 103, 467–476 (2008).

    CAS  Article  Google Scholar 

  11. 11

    Wu, H. et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115, 1029–1038 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Fantuzzi, G. Adipose tissue, adipokines, and inflammation. J. Allergy Clin. Immunol. 115, 911–919 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Duttlinger, R. et al. The Wsh and Ph mutations affect the c-kit expression profile: c-kit misexpression in embryogenesis impairs melanogenesis in Wsh and Ph mutant mice. Proc. Natl. Acad. Sci. USA 92, 3754–3758 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Eigen, H. et al. Evaluation of the addition of cromolyn sodium to bronchodilator maintenance therapy in the long-term management of asthma. J. Allergy Clin. Immunol. 80, 612–621 (1987).

    CAS  Article  Google Scholar 

  15. 15

    Paterson, W.G. Role of mast cell–derived mediators in acid-induced shortening of the esophagus. Am. J. Physiol. 274, G385–G388 (1998).

    CAS  PubMed  Google Scholar 

  16. 16

    Shin, H.Y., Kim, J.S., An, N.H., Park, R.K. & Kim, H.M. Effect of disodium cromoglycate on mast cell–mediated immediate-type allergic reactions. Life Sci. 74, 2877–2887 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Grimbaldeston, M.A. et al. Mast cell–deficient W-sash c-kit mutant KitW-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am. J. Pathol. 167, 835–848 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Koban, M. & Swinson, K.L. Chronic REM-sleep deprivation of rats elevates metabolic rate and increases UCP1 gene expression in brown adipose tissue. Am. J. Physiol. Endocrinol. Metab. 289, E68–E74 (2005).

    CAS  Article  Google Scholar 

  20. 20

    Santone, D.J., Shahani, R., Rubin, B.B., Romaschin, A.D. & Lindsay, T.F. Mast cell stabilization improves cardiac contractile function following hemorrhagic shock and resuscitation. Am. J. Physiol. Heart Circ. Physiol. 294, H2456–H2464 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Serna, H., Porras, M. & Vergara, P. Mast cell stabilizer ketotifen [4-(1-methyl-4-piperidylidene)-4h-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one fumarate] prevents mucosal mast cell hyperplasia and intestinal dysmotility in experimental Trichinella spiralis inflammation in the rat. J. Pharmacol. Exp. Ther. 319, 1104–1111 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Galli, S.J. & Kitamura, Y. Genetically mast-cell–deficient W/Wv and Sl/Sld mice. Their value for the analysis of the roles of mast cells in biologic responses in vivo. Am. J. Pathol. 127, 191–198 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Crandall, D.L., Hausman, G.J. & Kral, J.G. A review of the microcirculation of adipose tissue: anatomic, metabolic and angiogenic perspectives. Microcirculation 4, 211–232 (1997).

    CAS  Article  Google Scholar 

  24. 24

    Rupnick, M.A. et al. Adipose tissue mass can be regulated through the vasculature. Proc. Natl. Acad. Sci. USA 99, 10730–10735 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Pang, C. et al. Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity. Am. J. Physiol. Endocrinol. Metab. 295, E313–E322 (2008).

    CAS  Article  Google Scholar 

  26. 26

    Kintscher, U. et al. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler. Thromb. Vasc. Biol. 28, 1304–1310 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Sato, K. et al. Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res. 67, 9677–9684 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Skoura, A. et al. Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina. J. Clin. Invest. 117, 2506–2516 (2007).

    CAS  Article  Google Scholar 

  29. 29

    Xu, J. et al. Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J. Cell Biol. 154, 1069–1079 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Wang, B. et al. Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. J. Biol. Chem. 281, 6020–6029 (2006).

    CAS  Article  Google Scholar 

  31. 31

    Shi, G.P., Munger, J.S., Meara, J.P., Rich, D.H. & Chapman, H.A. Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. J. Biol. Chem. 267, 7258–7262 (1992).

    CAS  Google Scholar 

  32. 32

    Wolters, P.J. et al. Tissue-selective mast cell reconstitution and differential lung gene expression in mast cell-deficient KitW-sh/KitW-sh sash mice. Clin. Exp. Allergy 35, 82–88 (2005).

    CAS  Article  Google Scholar 

  33. 33

    Yang, M. et al. Cathepsin L activity controls adipogenesis and glucose tolerance. Nat. Cell Biol. 9, 970–977 (2007).

    CAS  Article  Google Scholar 

  34. 34

    Hadigan, C. et al. Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus–infected women. J. Clin. Endocrinol. Metab. 84, 1932–1937 (1999).

    CAS  PubMed  Google Scholar 

  35. 35

    Wild, R., Ramakrishnan, S., Sedgewick, J. & Griffioen, A.W. Quantitative assessment of angiogenesis and tumor vessel architecture by computer-assisted digital image analysis: effects of VEGF-toxin conjugate on tumor microvessel density. Microvasc. Res. 59, 368–376 (2000).

    CAS  Article  Google Scholar 

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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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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.

Corresponding author

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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