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 2

Fibγ390–396A, but not FibγΔ5, mice are protected from the development of HFD-driven obesity.

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Fibγ390–396A, but not FibγΔ5, mice are protected from the development o...
(A–G) WT and Fibγ390–396A mice were fed either a CD (n = 4 mice per genotype) or a 60% HFD (n = 9 mice per genotype). (A) Mean body weights of WT and fibrinogen γ390-396A (Fibγ390-396A) mice over a 20-week feeding period. (B and C) Distribution of body weights for WT and Fibγ390–396A mice fed the CD or 60% HFD at week 4 (B) and week 20 (C) on diet. (D and E) Analysis of body mass composition of 60% HFD–fed WT and Fibγ390–396A mice performed at week 12 (D) and week 16 (E). (F and G) Total fat pad weights of eWAT (F) and iWAT (G) for WT and Fibγ390–396A mice at week 20. (H) Mean body weights of WT and fibrinogen γΔ5 (FibγΔ5) mice fed a CD (n = 3 mice per genotype) or 60% HFD (n = 14–15 mice per genotype) over a 16-week feeding period. (I and J) Analysis of individual body weights for WT and FibγΔ5 mice at week 9 (I) and week 16 (J) on diet. (K and L) Total fat pad weights of eWAT (K) and iWAT (L) for WT and FibγΔ5 mice at week 16. Data are expressed as the mean ± SEM. Data were analyzed by 2-way ANOVA with Student-Newman-Keuls post hoc test. *P < 0.05, **P < 0.01 for analyses comparing differences between genotypes on the same diet. #P < 0.05, ##P < 0.01, ###P < 0.001 for analyses comparing differences between diets with mice of the same genotype.