Factor X – Protease-Activated Receptor-2 Signaling in the Regulation of Diet-Induced Obesity

The worldwide prevalence of overweight and obesity continues to increase each year, with a significant effect on physical and physiological health. Beyond regulation of blood clotting, coagulation proteins are known to modulate inflammatory responses predominantly via PARs and their crosstalk with several G-protein-coupled receptors (GCPRs) and non-GPCR receptors. To this end, coagulation proteases (FXa, FVIIa) and their receptors (TF-PAR2), which modulate systemic inflammation, constitute as potential targets. A study from Samad et al., 2013, showed that tissue factor (TF) and PAR2 signaling regulate insulin resistance (IR) and metabolic inflammation in mouse models of diet-induced obesity (DIO). For instance, adipocyte-specific TF-PAR2 signaling modulates AMP-activated protein kinase activation and energy expenditure promoting weight gain, while macrophage-specific TF-PAR2 signaling modulates metabolic inflammation and IR. Beside the role of adipose tissue and macrophages, the intestine also plays a critical role in the manifestation of DIO. However, the upstream proteases that modulate TF-PAR2 signaling, in a metabolic context within intestinal microenvironment, remain elusive. Both PAR2 and FXa are expressed within the intestinal epithelial cells (IECs). 

Dilraj Kaur discusses a study that aims to investigate the role of intestinal FXa-PAR2 axis in the regulation of DIO. In DIO settings, the current study has identified that intestinal FXa-PAR2 signaling regulates the early onset of obesity. Both PAR2 mutant mice, which is FXa signaling–resistant, and mice with IEC-specific deletion of FX showed reduced weight gain. However, unlike PAR2 mutant mice, mice with the IEC-specific deletion of FX were not protected against obesity-induced glucose intolerance. 

In conclusion, our study suggests that FXa-PAR2 signaling in the intestinal epithelium plays an important role in the regulation of the early onset of obesity. However, additional FX-like proteases or cell types may play a role in regulating glucose homeostasis.