Thrombin Promotes Diet-Induced Obesity Through Fibrin-Driven Inflammation

J Clin Invest. 2017 Aug 1;127(8):3152-3166. doi: 10.1172/JCI92744. Epub 2017 Jul 24.

Abstract

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.

MeSH terms

  • Adipose Tissue / metabolism
  • Adiposity
  • Amino Acid Motifs
  • Animals
  • Blood Glucose / metabolism
  • Body Composition
  • Body Weight
  • Coagulants / pharmacology
  • Dabigatran / pharmacology
  • Diet, High-Fat
  • Fatty Liver / metabolism
  • Female
  • Fibrin / metabolism*
  • Genotype
  • Homozygote
  • Inflammation / metabolism*
  • Liver / metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Obesity / metabolism*
  • Obesity / therapy*
  • Thrombin / metabolism*
  • Weight Gain

Substances

  • Blood Glucose
  • Coagulants
  • Fibrin
  • Thrombin
  • Dabigatran