Tissue factor, the initiator of the coagulation cascade, mediates coagulation factor VIIa-dependent activation of protease-activated receptor 2 (PAR2). Here we delineate a role for this signaling pathway in obesity and its complications. Mice lacking PAR2 (F2rl1) or the cytoplasmic domain of tissue factor were protected from weight gain and insulin resistance induced by a high-fat diet. In hematopoietic cells, genetic ablation of tissue factor-PAR2 signaling reduced adipose tissue macrophage inflammation, and specific pharmacological inhibition of macrophage tissue factor signaling rapidly ameliorated insulin resistance. In contrast, nonhematopoietic cell tissue factor-VIIa-PAR2 signaling specifically promoted obesity. Mechanistically, adipocyte tissue factor cytoplasmic domain-dependent VIIa signaling suppressed Akt phosphorylation with concordant adverse transcriptional changes of key regulators of obesity and metabolism. Pharmacological blockade of adipocyte tissue factor in vivo reversed these effects of tissue factor-VIIa signaling and rapidly increased energy expenditure. Thus, inhibition of tissue factor signaling is a potential therapeutic avenue for improving impaired metabolism and insulin resistance in obesity.