Department of Cell Biology, Torrey Pines Institute for Molecular Studies, San Diego, California, USA.
Nat Med. 2011 Oct 23;17(11):1490-7. doi: 10.1038/nm.2461.
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.
组织因子是凝血级联反应的启动子，介导凝血因子 VIIa 依赖性蛋白酶激活受体 2（PAR2）的激活。在这里，我们描述了这种信号通路在肥胖及其并发症中的作用。缺乏 PAR2（F2rl1）或组织因子细胞质结构域的小鼠可防止高脂肪饮食引起的体重增加和胰岛素抵抗。在造血细胞中，组织因子-PAR2 信号的遗传缺失可减少脂肪组织巨噬细胞炎症，而巨噬细胞组织因子信号的特异性药理学抑制可迅速改善胰岛素抵抗。相比之下，非造血细胞组织因子-VIIa-PAR2 信号特异性促进肥胖。从机制上讲，脂肪细胞组织因子细胞质结构域依赖性 VIIa 信号抑制 Akt 磷酸化，同时肥胖和代谢关键调节因子的转录发生不良变化。体内药理学阻断组织因子可逆转组织因子-VIIa 信号的这些作用，并迅速增加能量消耗。因此，抑制组织因子信号可能是改善肥胖症中代谢受损和胰岛素抵抗的一种潜在治疗途径。
