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

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 9

Treatment of mice with DE protects against the development of HFD-driven obesity and limits progression of established obesity.

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Treatment of mice with DE protects against the development of HFD-driven...
(A–C) Mice were fed a CD, a CD formulated with the direct thrombin inhibitor dabigatran etexilate (DE, 7.5 mg/g), a 60% HFD, or a 60% HFD with DE (7.5 mg/g) (n = 9–10 mice per group). (A) Mean body weights of mice over a 20-week feeding period. (B) Body mass composition analysis for fat mass at week 12 on diet. (C) Distribution of body weights at week 20 on diet. (D) Fibrin(ogen) species were detected in clots formed in vitro with plasma from WT and F13a1–/– mice using a capillary Western blot approach. Levels of fibrin(ogen) species were also detected in extracts of eWAT from 20-week CD- and HFD-fed control and DE-treated mice. For quantification, eWAT was used from n = 3–4 mice for CD and n = 7 for HFD. (E and F) WT mice were fed a CD or a 60% HFD for 12 weeks, after which the mice received the same diet for an additional 8 weeks but were randomized to receive diet with or without DE. (E) Summary of experimental design strategy and feeding schedule for the DE rescue experiment. (F) Change in body weight over time for the 8 weeks of DE treatment. Data are expressed as the mean ± SEM. Data were analyzed by 2-way ANOVA with Student-Newman-Keuls post hoc test. *P < 0.05 for analyses comparing differences between HFD and HFD+DE. #P < 0.05, ##P < 0.01 for analyses comparing differences between HFD and CD or between HFD+DE and CD+DE. For the DE intervention study, †P < 0.05 for mice fed a HFD versus CD (neither with DE); ‡P < 0.05 for mice on the same diet not treated with DE.