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: Jian Liu, Adeline Divoux, Jiusong Sun, Jie Zhang, Karine Clément, Jonathan N Glickman, Galina K Sukhova, Paul J Wolters, Juan Du, Cem Z Gorgun, Alessandro Doria, Peter Libby, Richard S Blumberg, Barbara B Kahn, Gökhan S Hotamisligil, Guo-Ping Shi
• Journal: Nature medicine (Nat Med) Vol. 15 Issue 8 Pg. 940-5 (Aug 2009) ISSN: 1546-170X [Electronic] United States
• PMID: 19633655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-kit
• Cromolyn Sodium

Topics

• Animals
• Cromolyn Sodium (therapeutic use)
• Diabetes Mellitus, Experimental (drug therapy, etiology, genetics, immunology)
• Diabetes Mellitus, Type 2 (complications, drug therapy, genetics, immunology)
• Diet, Atherogenic
• Drug Evaluation, Preclinical
• Female
• Humans
• Male
• Mast Cells (drug effects, metabolism)
• Mice
• Mice, Transgenic
• Obesity (complications, drug therapy, etiology, genetics, immunology)
• Organ Specificity (genetics)
• Proto-Oncogene Proteins c-kit (genetics, metabolism)