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 6

Fibγ390–396A mice are protected from the development of HFD-driven fatty liver disease and hepatocellular injury.

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Fibγ390–396A mice are protected from the development of HFD-driven fatt...
WT and Fibγ390–396A mice were fed either a CD (n = 4 per genotype) or a 60% HFD (n = 12 per genotype) for 20 weeks. (A) Representative H&E-stained and fibrin(ogen) (red) immunohistochemistry–stained sections of liver tissue. Note that liver tissue from HFD-fed WT mice revealed evidence of hepatic steatosis and sinusoidal fibrin(ogen) deposits. Scale bars: 100 μm. (B) Total liver weights of mice following the 20-week diet challenge. (C) Quantification of fibrin deposits in CD-fed (n = 4 per genotype) and HFD-fed (n = 8 per genotype) WT and Fibγ390–396A mice. Data are presented as the mean ± SEM of the percent area of staining per high-powered field. (D) Analysis of liver triglyceride content confirmed significantly diminished hepatic steatosis in HFD-fed Fibγ390–396A mice relative to WT animals. (E) Analysis of circulating alanine aminotransferase (ALT) in CD- and HFD-fed WT and Fibγ390–396A mice indicated significantly reduced hepatocellular damage in HFD-fed Fibγ390–396A mice. (F–K) Hepatic levels of mRNA in liver tissue encoding the genes Adgre1 (F), Ccl2 (G), Tnf (H), Pparg (I), Cidea (J), and Cd36 (K) were determined by quantitative RT-PCR. 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, ***P < 0.001 for analyses comparing differences between genotypes on the same diet. #P < 0.05, ##P < 0.01 for analyses comparing differences between diets with mice of the same genotype.