Tissue factor-PAR2 signaling promotes diet-induced obesity and adipose inflammation

Tissue factor (TF), the initiator of the coagulation cascade, mediates coagulation factor VIIa-dependent activation of protease activated receptor-2 (PAR2). Here we delineate an unexpected role for coagulation signaling in obesity and its complications. Mice lacking PAR2 (F2rl1) or the cytoplasmic domain of TF (F3) are protected from high fat diet (HFD) induced weight gain and insulin resistance. In hematopoietic cells, genetic deletion of TF-PAR2 signaling reduces adipose tissue macrophage inflammation and specific pharmacological inhibition of macrophage TF signaling rapidly ameliorates insulin resistance. In contrast, non-hematopoietic cell TF-VIIa-PAR2 signaling specifically promotes obesity. Mechanistically, adipocyte TF cytoplasmic domain dependent VIIa signaling suppresses Akt phosphorylation with concordant adverse transcriptional changes of key regulators of obesity and metabolism. Pharmacological blockade of adipocyte TF in vivo reverses these effects of TF-VIIa signaling and rapidly improves energy expenditure. Thus, TF signaling is a potential therapeutic target to improve impaired metabolism and insulin resistance in obesity.