TRP X33 - Protease-selective signaling via protease activated receptor-2 in regulation of metabolic adaptation in the gut

Funding period: 01.03.2019 – 31.08.2020

Project Summary

Nutrient excess in obesity drives metabolic reprogramming in multiple tissues involving extensive inter-organ and inter-cellular crosstalk. Experimental and clinical studies show that prolonged nutrient excess often compromises metabolic adaptation propagating pro-obesogenic and pro-inflammatory responses. Chronic inflammation further promotes insulin resistance and associated co-morbidities. Obesity and type 2 diabetes is characterized by a hypercoagulable state and clinical studies show a strong correlation of markers of coagulation activation in metabolic disorders. Coagulation protease-dependent signaling via protease-activated receptors are intimately associated with inflammation. The experimental evidence supports roles of tissue factor and G protein coupled -protease activated receptor-2 signaling in regulation of IR and metabolic inflammation in diet-induced obesity. Likewise, increase in plasminogen activator inhibitor-1 levels and fibrin-driven inflammation promote insulin resistance in obesity. Additionally, impaired thrombomodulin-dependent protein C activation is mechanistically linked to diabetic kidney disease. Given, the increased usage of direct oral anticoagulants, understanding the role of specific coagulation proteases in regulation of metabolic inflammation is highly relevant and might provide insights into the design of novel treatment regimens for patients suffering from thrombo-inflammatory and cardio-metabolic disorders.

By utilizing newly developed PAR2 mutant mice and mice with intestinal-epithelial cell specific deletions of specific proteases, we aim to investigate the role of protease-specific signaling via PAR2 in regulation of postprandial metabolic events and gut permeability in healthy and in the mouse models of diet-induced obesity.

Principle Investigator