Epithelial TMPRSS2 impairs glucose homeostasis in obese mice by regulating ghrelin-GLP-1 receptor signaling pathway.

Glucagon-like peptide-1 (GLP-1) and glucose-induced insulinotropic polypeptide (GIP) receptor agonists have revolutionized obesity therapy, but causes of obesity-associated dysregulation of endogenous incretin production remain incompletely understood. Here we show that intestinal transmembrane serine protease 2 (TMPRSS2) plays a pivotal role in deregulating anti-diabetic GLP-1 production in obesity. TMPRSS2 is widely coexpressed in intestinal epithelial cells along with its signaling target protease-activated receptor 2 (PAR2). In addition to its role in regulating coagulation protease-mediated adipose tissue inflammation, PAR2 signaling in the gut controls postprandial GIP secretion. TMPRSS2, but not the epithelial cell-expressed proteases FXa or matriptase, activates PAR2 and thereby promotes postprandial GIP release. Accordingly, a PAR2-mutant mouse resistant to TMPRSS2 cleavage is protected from GIP upregulation and diet-induced obesity. In the context of obesity, TMPRSS2 also attenuates bioavailability of the ghrelin pathway and thereby suppresses GLP-1-mediated control of glucose homeostasis. Pharmacological inhibition or genetic deletion of TMPRSS2 restores ghrelin signaling-dependent GLP-1 secretion and GLP-1's anti-diabetic effects on nutritional glucose homeostasis. Thus, epithelial cell-expressed TMPRSS2, which critically contributes to the lung pathology in SARS-CoV-2 infection, emerges as an intestinal incretin regulator and a potential link between infection and chronic cardiometabolic diseases.