OC 28.1 - Factor X - Protease activated receptor-2 signaling in the regulation of diet-induced obesity

Background: Tissue factor (TF) and PAR2 signaling regulate insulin resistance (IR) and metabolic inflammation in mouse models of diet-induced obesity (DIO). While TF-PAR2 signaling in adipocytes regulates IR, TF-PAR2 signaling in monocyte/macrophages regulates metabolic inflammation. However, the proteases that modulate TF-PAR2 signaling remain unclear. TF together with coagulation factor FXa, FVIIa, and endothelial protein C receptor (EPCR) forms distinct ternary or binary protein complexes that modulate PAR2 signaling in a cell-specific manner. Beyond adipose tissue and macrophages, the intestine also plays a critical role in the manifestation of DIO.

Aims: Given that both PAR2 and FXa are expressed in the intestinal epithelial cells, we aimed to investigate the role of the intestinal FXa-PAR2 axis in the regulation of DIO.

Methods: For this study, we employed FXa/FVIIa signaling resistant PAR2 mutant (PAR2-G37I) mice and a complementary mouse model with intestinal epithelial cell specific-FX deletion (FX^fl/fl Villin^cre). These mice were fed a high-fat diet (HFD) for 16 weeks and features of DIO including weight gain, glucose tolerance, and insulin sensitivity were determined. Tissue samples were harvested for ex vivo analysis.

Results: Upon HFD feeding, when compared to wild-type (WT) mice, PAR2-G37I mutant mice showed reduced weight gain and improved glucose tolerance. These changes were associated with a specific reduction in the postprandial intestinal hormone; glucose-dependent insulinotropic polypeptide (GIP). In contrast, no difference in glucagon-like peptide (GLP-1) levels was observed. Incongruent with PAR2-G37I mutants, FX^fl/fl Villin^cre mice showed reduced early-onset obesity and a specific reduction of postprandial GIP. Despite reduced weight gain, FX^fl/fl Villin^cre mice were not protected against obesity-induced glucose intolerance when compared to HFD-fed FX^fl/fl control mice.

Conclusion(s): These results suggest that FXa-PAR2 signaling in the intestinal epithelium plays an important role in the regulation of postprandial hormone GIP and early-onset obesity. However, additional proteases or cell types may play a role in regulating glucose homeostasis.