Effect of Fibrin Degradation Products on Inflammation and Adipocyte Glucose Disposal

Obesity, the most predominant disease in the world, is strongly associated with chronic inflammation which is directly correlated with insulin resistance (IR). Obesity also results in hyperfibrinogenemia. Fibrinogen, a glycoprotein involved in coagulation, is converted to fibrin via thrombin to form a blood clot and fibrin is degraded into two D (FDP-D) and one E (FDP-E) fragment by plasmin. Previous studies show that fibrinogen and fibrin induce inflammation but effect of FDP is unknown. FDP-D is used as a biomarker of hypercoagulability and has less bioactivity so we decided to focus on examining the effect of FDP-E on inflammation and adipocyte glucose disposal. First, cytokine mRNA expression in primary macrophages treated with FDP-E was measured and the results showed that FDP-E induces inflammation (55.9±7.1 fold change in MCP-1). RAW264.7 macrophages and 3T3-L1 adipocytes were treated with FDP-E from 0- to 100nM or for different times from 1 to 12 hours. FDP-E had the greatest effect at 100nM for 6 hours in both macrophages (29.5±9.8 fold change in MCP-1) and adipocytes (11.3±3.1 fold change in MCP-1). Next, adipocytes were treated with increasing concentrations of conditioned medium from FDP-E treated macrophages or FDP-E itself to assess the indirect or direct effects on glucose uptake. After 24 hours, the capacity for glucose uptake using radiolabeled 3H-2-deoxy-D-glucose was determined. There was no significant difference in conditioned medium treated cells but FDP-E itself suppressed insulin stimulated glucose uptake significantly (71% reduction; p=0.00001). We found that FDP-E induces inflammation in macrophages and adipocytes and decreases glucose uptake in adipocytes. From these results, we can conclude that FDP-E could be a key molecule in obesity, inflammation, and insulin resistance.