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 5

Fibγ390–396A mice fed a HFD for 20 weeks have significantly fewer F4/80+ macrophages and reduced adipocyte size relative to HFD-fed WT mice.

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Fibγ390–396A mice fed a HFD for 20 weeks have significantly fewer F4/80...
(A) Tissue sections of eWAT from WT and Fibγ390–396A mice fed either a CD or a 60% HFD for 20 weeks were stained by immunohistochemistry for the macrophage marker F4/80. Note that F4/80+ cells (arrows) accumulated in “crown-like” structures similar to the fibrin(ogen) deposits shown in Figure 1. Scale bars: 50 μm. (B) Quantification of the number of F4/80+ cells per ×5 high-powered field in eWAT of WT and Fibγ390–396A mice fed CD (n = 3 per genotype) and HFD (n = 5 per genotype). Note that 10 fields were evaluated per sample. (C) Quantification of adipocyte area in the eWAT of WT and Fibγ390–396A mice fed CD (n = 3 per genotype) and HFD (n = 5 per genotype). Note that the area of 50 adipocytes per sample was determined. Data in B and C are presented as 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.