Faculty Collaboration Database

Elimination of fibrin polymer formation or crosslinking, but not fibrinogen deficiency, is protective against diet-induced obesity and associated pathologies. J Thromb Haemost 2022 Dec;20(12):2873-2886

Date

09/17/2022

Pubmed ID

36111375

Pubmed Central ID

PMC9669152

DOI

10.1111/jth.15877

Scopus ID

2-s2.0-85139491210 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

BACKGROUND: Obesity predisposes individuals to metabolic syndrome, which increases the risk of cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes. A pathological manifestation of obesity is the activation of the coagulation system. In turn, extravascular fibrin(ogen) deposits accumulate in adipose tissues and liver. These deposits promote adiposity and downstream sequelae by driving pro-inflammatory macrophage function through binding the leukocyte integrin receptor α_M β₂ .

OBJECTIVES: An unresolved question is whether conversion of soluble fibrinogen to a crosslinked fibrin matrix is required to exacerbate obesity-driven diseases.

METHODS: Here, fibrinogen-deficient/depleted mice (Fib- or treated with siRNA against fibrinogen [siFga]), mice expressing fibrinogen that cannot polymerize to fibrin (Fib^AEK ), and mice deficient in the fibrin crosslinking transglutaminase factor XIII (FXIII-) were challenged with a high-fat diet (HFD) and compared to mice expressing a mutant form of fibrinogen lacking the α_M β₂ -binding domain (Fib𝛾^390-396A ).

RESULTS AND CONCLUSIONS: Consistent with prior studies, Fib𝛾^390-396A mice were significantly protected from increased adiposity, NAFLD, hypercholesterolemia, and diabetes while Fib- and siFga-treated mice gained as much weight and developed obesity-associated pathologies identical to wildtype mice. Fib^AEK and FXIII- mice displayed an intermediate phenotype with partial protection from some obesity-associated pathologies. Results here indicate that fibrin(ogen) lacking α_M β₂ binding function offers substantial protection from obesity and associated disease that is partially recapitulated by preventing fibrin polymer formation or crosslinking of the wildtype molecule, but not by reduction or complete elimination of fibrinogen. Finally, these findings support the concept that fibrin polymerization and crosslinking are required for the full implementation of fibrin-driven inflammation in obesity.

Author List

Hur WS, King KC, Patel YN, Nguyen YV, Wei Z, Yang Y, Juang LJ, Leung J, Kastrup CJ, Wolberg AS, Luyendyk JP, Flick MJ

Author

Christian Kastrup PhD, MS Professor in the Surgery department at Medical College of Wisconsin

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

Afibrinogenemia
Animals
Diabetes Mellitus, Type 2
Diet
Factor XIII
Fibrin
Fibrinogen
Hemostatics
Mice
Non-alcoholic Fatty Liver Disease
Obesity
Polymers