Mast cell protease-4 mediates obesity-related metabolic dysregulation via negative effect on adiponectin levels

Objectives: 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) in obesity and insulin resistance development.

Methods: Mcpt4 defficient mice (mcpt4-/-) and control mice were fed a high fat diet in diet-induced obesity (DIO) experiment or a normal diet. Mice were tested for glucose tolerance and insuline resistance and levels of several obesity related markers were measured in serum or plasma. Adipose tissue (AT) was tested for inflammation by qPCR and flow cytometry. In vitro assays using 3T3L1 adipocytes were employed to disclose the mechanisms of observed phenotype.

Results: Mcpt4-defficiency was associated with improved glucose tolerance and improved insulin sensitivity in DIO despite having higher body weight. A similar trend in glucose tolerance was already observed with mice under normal diet. No difference between the two groups was observed in AT inflammation. Serum level of adiponectin was significantly higher in mcpt4-/- mice and its content in AT was also increased in mcpt4-/- as compared to control mice. In in vitro experiments we found that chymase inhibits the expression of adiponectin by adipocytes. Furthermore, direct adiponectin cleavage by chymase was identified.

Conclusion: Mast cell chymase negatively affects glucose metabolism and insulin resistance by an AT inflammation independent mechanism. The mechanism can be connected with chymase directly affecting adiponectin levels.