title: 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 responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. 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-gamma (IFN-gamma), 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.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Adeline
authors.initials: A
authors.lastname: Divoux
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Glickman
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Cem Z
authors.initials: CZ
authors.lastname: Gorgun
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D004205:Cromolyn Sodium / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D004036:Diet, Atherogenic; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D009928:Organ Specificity / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D004205:Cromolyn Sodium