Guo-Ping Shi, DSc.

Role of mast cells in obesity and diabetes

Mast cells are essential effector cells in eliciting allergic responses by releasing cytoplasmic granules (1,2).  Our recent studies demonstrate that mast cells participate in human pathobiology beyond allergic inflammation in the context of atherosclerosis and abdominal aortic aneurysm formation (3-5). Obesity is closely associated with these vascular diseases.  In human and mouse white adipose tissues (WAT), >90% of the inflammatory cytokines (also named “adipokines”) are not from adipocytes, but are produced by the non-fat stromal vascular fraction, which contains macrophages, lymphocytes, EC (6-10), and probably mast cells.  We hypothesized that mast cells play critical roles to both obesity and diabetes.

1).  Mast cells and human obesity.            Using WAT from lean and obese human subjects, we detected high numbers of mast cells in WAT from obese subjects, but many fewer in those from lean subjects.  Using our newly developed ELISA technique, we found that obese subject serum contain significantly higher amount of mast cell-specific tryptases than those in serum from lean donors.  Our current study focuses on the hypothesis that human mast cell activities associate with both obesity and diabetes.

2).  Mast cell deficiency or inactivation reduces both obesity and diabetes.                If mast cells are essential to obesity, inactivation of mast cells in humans or animals should prevent obesity development.  This hypothesis was proved in diet-induced mouse obesity model.  After 3~6 months of a high fat diet, all wild-type (WT) mice gained body weight, whereas mast cell-deficient KitW-sh/W-sh mice gained significantly less than the WT counterparts.  Along with reduced body weight, KitW-sh/W-sh mice also showed reduced WAT adipokine levels.  Importantly, KitW-sh/W-sh mice were highly sensitive to glucose and insulin challenges.  Compared with WT mice, KitW-sh/W-sh mice metabolized glucose responded to insulin stimulations much faster.  As in KitW-sh/W-sh mice, WT receiving small molecule mast cell inactivators (cromolyn or ketotifen) also demonstrated reduced body weight and increased sensitivity to glucose.  Most interestingly, cromolyn and ketotifen also improved preformed obesity and diabetes.  After 12 weeks of a high fat diet, all WT mice became obese and diabetic.  Both symptoms were reversed significantly after mice received these drugs.  Such significant effects of these drugs were not because that the drugs were toxic to the mice.  Indeed, mast cell deficiency or inactivation increased mouse energy expenditures. Further, mast cell also control adipose tissue growth by regulating protease expression and angiogenesis.  WAT from KitW-sh/W-sh mice or those treated with mast cell inactivators contain significantly less cystinyl protease activities and microvessel numbers.  Our future goal is to investigate whether the same role of mast cells apply to monkeys and humans.

4).  Mast cell cytokines contribute to obesity and diabetes.   Mast cell granules contain cytokine, chemokines, growth factors, and proteases, etc.  Using mast cell reconstitution into KitW-sh/W-sh mice, we demonstrated that mast cells release pro-inflammatory cytokines to control both body weight gain and glucose metabolism.  Reduced body weight and glucose tolerance in KitW-sh/W-sh mice can be reversed by reconstitution with mast cell isolated from WT mice, but not those from cytokine (e.g. IL6 and IFN-g) knockout mice.  Correlated with body weight gain and glucose tolerance, WT mast cell reconstitution to cromolyn also reversed serum leptin, insulin, and glucose levels to those of obese and diabetic mice.  These observations explained why stabilization of mast cells by cell inactivators (cromolyn or ketotifen) reduced body weight gain and improved diabetes.  Further studies are planned to identify more important mast cell mediators to obesity and diabetes, to characterize the molecules responsible for mast cell recruitment to the WAT, and analyze mast cell-WAT stromal cell interactions.