Mast cell protease-4 mediates obesity-related metabolic dysregulation in mice by targetting body levels of adiponectin

Mast cells were recently found as key players in obesity-related metabolic dysregulation. Our study addresses the role of mast cell protease-4 (mcpt4, the mouse counterpart of human chymase, which is an important mast cell secreted protease) in obesity and insulin resistance development. The levels of mcpt4 expression were dramatically elevated in obese adipose tissue (AT), when compared to lean AT of C57BL/6 mice. Therefore, mcpt4 defficient mice (mcpt4-/-) and control mice were fed a high fat diet in diet-induced obesity (DIO) experiment. Despite increased weight gain, mcpt4-defficiency was associated with improved glucose tolerance and improved insulin sensitivity. No difference in AT inflammation between the two genotypes was found, as assessed by studying inflammatory cells by flow cytometry and the expression of metabolic and inflammatory genes in subcutaneous and epidydimal AT of mcpt4-/- or control mice. Serum level of adiponectin was significantly elevated in mcpt4-/- mice, but no significant difference in adipocyte size was observed. In vitro experiments with 3T3-L1 adipocytes revealed that chymase inhibits the expression of adiponectin. Direct cleavage of adiponectin by chymase is another possible mechanism currently addressed. Together, mast cell chymase negatively affects glucose metabolism. The mechanism could be linked to the chymase effect on adiponectin levels.