Kopec Anna K, Abrahams Sara R, Thornton Sherry, Palumbo Joseph S, Mullins Eric S, Divanovic Senad, Weiler Hartmut, Owens A Phillip, Mackman Nigel, Goss Ashley, van Ryn Joanne, Luyendyk James P, Flick Matthew J
Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA.
Division of Experimental Hematology and Cancer Biology.
J Clin Invest. 2017 Aug 1;127(8):3152-3166. doi: 10.1172/JCI92744. Epub 2017 Jul 24.
Obesity promotes a chronic inflammatory and hypercoagulable state that drives cardiovascular disease, type 2 diabetes, fatty liver disease, and several cancers. Elevated thrombin activity underlies obesity-linked thromboembolic events, but the mechanistic links between the thrombin/fibrin(ogen) axis and obesity-associated pathologies are incompletely understood. In this work, immunohistochemical studies identified extravascular fibrin deposits within white adipose tissue and liver as distinct features of mice fed a high-fat diet (HFD) as well as obese patients. Fibγ390-396A mice carrying a mutant form of fibrinogen incapable of binding leukocyte αMβ2-integrin were protected from HFD-induced weight gain and elevated adiposity. Fibγ390-396A mice had markedly diminished systemic, adipose, and hepatic inflammation with reduced macrophage counts within white adipose tissue, as well as near-complete protection from development of fatty liver disease and glucose dysmetabolism. Homozygous thrombomodulin-mutant ThbdPro mice, which have elevated thrombin procoagulant function, gained more weight and developed exacerbated fatty liver disease when fed a HFD compared with WT mice. In contrast, treatment with dabigatran, a direct thrombin inhibitor, limited HFD-induced obesity development and suppressed progression of sequelae in mice with established obesity. Collectively, these data provide proof of concept that targeting thrombin or fibrin(ogen) may limit pathologies in obese patients.
肥胖会引发一种慢性炎症和高凝状态，进而导致心血管疾病、2型糖尿病、脂肪肝疾病以及多种癌症。凝血酶活性升高是肥胖相关血栓栓塞事件的基础，但凝血酶/纤维蛋白（原）轴与肥胖相关病理之间的机制联系尚未完全明确。在这项研究中，免疫组织化学研究发现，白色脂肪组织和肝脏中的血管外纤维蛋白沉积是高脂饮食（HFD）喂养小鼠以及肥胖患者的显著特征。携带无法结合白细胞αMβ2整合素的纤维蛋白原突变形式的Fibγ390 - 396A小鼠可免受HFD诱导的体重增加和肥胖加剧的影响。Fibγ390 - 396A小鼠的全身、脂肪和肝脏炎症明显减轻，白色脂肪组织中的巨噬细胞数量减少，并且几乎完全免受脂肪肝疾病和葡萄糖代谢紊乱的影响。纯合血栓调节蛋白突变体ThbdPro小鼠的凝血酶促凝功能增强，与野生型小鼠相比，在喂食HFD时体重增加更多，脂肪肝疾病也更加严重。相比之下，直接凝血酶抑制剂达比加群治疗可限制HFD诱导的肥胖发展，并抑制已患肥胖症小鼠后遗症的进展。总体而言，这些数据提供了概念验证，即靶向凝血酶或纤维蛋白（原）可能会限制肥胖患者的病理状况。
