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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\u2013mediated adipose tissue inflammation, PAR2 signaling in the gut controls postprandial GIP secretion. TMPRSS2, but not the epithelial cell\u2013expressed 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\u2013mediated control of glucose homeostasis. Pharmacological inhibition or genetic deletion of TMPRSS2 restores ghrelin signaling\u2013dependent GLP-1 secretion and GLP-1\u2019s anti-diabetic effects on nutritional glucose homeostasis. Thus, epithelial cell\u2013expressed 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.<\/jats:p>\n                  <jats:p\/>\n                  <jats:p>GLP-1 based therapeutics revolutionized anti-diabetic and anti-obesity treatments. 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