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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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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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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