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

Dilraj Kaur1, Sagarika Chakrabarty2, Claudius Witzler1

  • 1Center for Thrombosis and Hemostasis (CTH), Medical Centre of the Johannes Gutenberg University, Mainz, Germany.

JCI Insight
|March 17, 2026
PubMed

Insights

Transmembrane serine protease 2 (TMPRSS2) in the gut deregulates incretin production, worsening obesity and glucose control. Inhibiting TMPRSS2 restores incretin signaling, offering a potential therapeutic target for obesity and related metabolic diseases.

Area of Science:

  • Gastroenterology
  • Metabolic Diseases
  • Molecular Biology

Background:

  • Glucagon-like peptide-1 (GLP-1) and glucose-induced insulinotropic polypeptide (GIP) receptor agonists are effective obesity treatments, but the causes of altered endogenous incretin production in obesity are unclear.
  • Intestinal epithelial cells (IECs) express proteases like TMPRSS2 and its target PAR2, which are implicated in metabolic regulation and inflammation.

Purpose of the Study:

  • To investigate the role of intestinal transmembrane serine protease 2 (TMPRSS2) in regulating endogenous incretin production and its impact on obesity and glucose homeostasis.
  • To explore TMPRSS2's mechanism of action via protease activated receptor 2 (PAR2) signaling in the gut.

Main Methods:

  • Utilized a PAR2 mutant mouse model resistant to TMPRSS2 cleavage.
  • Investigated the effects of pharmacological inhibition and genetic deletion of TMPRSS2 on incretin secretion and glucose homeostasis.
  • Assessed the impact of TMPRSS2 on ghrelin pathway bioavailability and GLP-1 signaling.

Main Results:

  • TMPRSS2 activates PAR2 in the gut, promoting postprandial GIP release and contributing to diet-induced obesity.
  • A PAR2 mutant mouse model resistant to TMPRSS2 was protected from GIP upregulation and obesity.
  • In obesity, TMPRSS2 impairs ghrelin pathway bioavailability, suppressing GLP-1 secretion and its glucose-lowering effects.
  • Inhibition or deletion of TMPRSS2 restored ghrelin-dependent GLP-1 secretion and anti-diabetic effects.

Conclusions:

  • Epithelial TMPRSS2 is a key regulator of intestinal incretins (GLP-1 and GIP), influencing obesity and glucose homeostasis.
  • TMPRSS2 represents a potential therapeutic target for metabolic diseases, linking gut health, infection (e.g., SARS-CoV-2), and cardiometabolic disorders.
Keywords:
CoagulationG protein-coupled receptorsInflammationMetabolismProteasesVascular biology

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