Elimination of fibrin polymer formation or crosslinking, but not fibrinogen deficiency, is protective against diet-induced obesity and associated pathologies

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 alpha(M)beta(2). 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 alpha(M)beta(2)-binding domain (Fib gamma(390-396A)). Results and Conclusions: Consistent with prior studies, Fib gamma(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 alpha(M)beta(2) 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.

Automated summary

It has been found that the lack of fibrinogen with binding function to the leukocyte integrin receptor can substantially reduce obesity and associated diseases, while preventing fibrinogen polymerization or crosslinking only partially replicates this protective effect.