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 for 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 co-expressed in intestinal epithelial cells (IEC) 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-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 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.