Format

Send to

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

Thrombin promotes diet-induced obesity through fibrin-driven inflammation.

Author information

1
Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA.
2
Division of Experimental Hematology and Cancer Biology.
3
Division of Rheumatology.
4
Division of Hematology, and.
5
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
6
Department of Physiology, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
7
Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
8
Thrombosis and Hemostasis Program, Division of Hematology and Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
9
Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.
10
Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH, Biberach, Germany.

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.

PMID:
28737512
PMCID:
PMC5531415
DOI:
10.1172/JCI92744
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center