Faculty Collaboration Database

Thrombin promotes diet-induced obesity through fibrin-driven inflammation. J Clin Invest 2017 Aug 01;127(8):3152-3166

Date

07/25/2017

Pubmed ID

28737512

Pubmed Central ID

PMC5531415

DOI

10.1172/JCI92744

Scopus ID

2-s2.0-85026626202 (requires institutional sign-in at Scopus site)   88 Citations

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.

Author List

Kopec AK, Abrahams SR, Thornton S, Palumbo JS, Mullins ES, Divanovic S, Weiler H, Owens AP 3rd, Mackman N, Goss A, van Ryn J, Luyendyk JP, Flick MJ

Author

Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adipose Tissue
Adiposity
Amino Acid Motifs
Animals
Blood Glucose
Body Composition
Body Weight
Coagulants
Dabigatran
Diet, High-Fat
Fatty Liver
Female
Fibrin
Genotype
Homozygote
Inflammation
Liver
Macrophages
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Obesity
Thrombin
Weight Gain