Letter abstract
Nature Medicine 15, 940 - 945 (2009)
Published online: 26 July 2009 | doi:10.1038/nm.1994
Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice
Jian Liu1, Adeline Divoux2, Jiusong Sun1, Jie Zhang1, Karine Clément2,3,4, Jonathan N Glickman1, Galina K Sukhova1, Paul J Wolters5, Juan Du1, Cem Z Gorgun6, Alessandro Doria7, Peter Libby1, Richard S Blumberg1, Barbara B Kahn8, Gökhan S Hotamisligil6 & Guo-Ping Shi1
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-
(IFN-), 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.
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
- Institut National de la Santé et de la Recherche Médicale, U872, Nutriomique, Paris, France.
- University Pierre and Marie Curie-Paris 6, Cordeliers Research Center, Paris, France.
- Assistance Publique-Hôpitaux de Paris, Nutrition Department, Pitié-Salpetrière Hospital, Paris, France.
- Department of Medicine, University of California, San Francisco, California, USA.
- Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, Massachusetts, USA.
- Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA.
- Department of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Correspondence to: Guo-Ping Shi1 e-mail: gshi@rics.bwh.harvard.edu
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