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

Abstract

Mast cells, which are involved in inflammation and wound healing, have now been shown to have a role in obesity and diabetes in a new report by Guo-Ping Shi and his colleagues. They go on to show that pharmacological inhibition of mast cell function is sufficient to reduce these metabolic disturbances in mice, suggesting a new therapeutic avenue in the clinic for these disorders. 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.