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Thrombin promotes diet-induced obesity through fibrin-driven inflammation
Anna K. Kopec, … , James P. Luyendyk, Matthew J. Flick
Anna K. Kopec, … , James P. Luyendyk, Matthew J. Flick
Published July 24, 2017
Citation Information: J Clin Invest. 2017;127(8):3152-3166. https://doi.org/10.1172/JCI92744.
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Research Article Hematology Inflammation

Thrombin promotes diet-induced obesity through fibrin-driven inflammation

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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.

Authors

Anna K. Kopec, Sara R. Abrahams, Sherry Thornton, Joseph S. Palumbo, Eric S. Mullins, Senad Divanovic, Hartmut Weiler, A. Phillip Owens III, Nigel Mackman, Ashley Goss, Joanne van Ryn, James P. Luyendyk, Matthew J. Flick

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Figure 1

Fibrin(ogen) deposits accumulate in white adipose tissue of HFD-fed mice and obese human patients as well as in liver tissue of HFD-fed mice and patients with NASH.

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Fibrin(ogen) deposits accumulate in white adipose tissue of HFD-fed mice...
(A) Fibrin(ogen) immunohistochemical staining (red) of white adipose tissue of mice fed either a control diet (CD) or a 60% high-fat diet (HFD) for 16 weeks as well as visceral adipose tissue of nonobese and obese patients. Note the intense fibrin(ogen) deposits in areas between the hypertrophic adipocytes coincident with macrophages (arrows). (B) Fibrin(ogen) staining (red) of liver tissue from mice fed either a CD or a 60% HFD for 16 weeks as well as from patients with normal liver histology or obese patients with NASH. Scale bars: 100 μm.
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