Abstract 13427: Treatment With a Direct Thrombin Inhibitor Interrupts the Progression of Obesity-Associated Pathologies in Mice Fed a High Fat Diet (Best of Basic Science Abstract)

Abstract

Obesity is accompanied by activation of the coagulation cascade in humans and in experimental settings of diet-induced obesity. Genetic and pharmacologic interference with thrombin proteolytic activity has previously been shown to attenuate obesity-associated pathologies, including non-alcoholic fatty liver disease (NAFLD). In this study we sought to determine if intervention with the thrombin inhibitor, dabigatran etexilate (DE), can slow the progression of NAFLD and obesity when administered after onset of disease. Wild-type C57BL/6J mice were fed a control diet (AIN-93M, 10% calories from soybean oil) or a high fat diet (HFD, 60% calories from lard and soybean oil) for 3 months and then switched to identical diets containing 7.5 mg/g DE (AIN-93M+DE and HFD+DE) for an additional 2 months (intervention groups). Additional groups of mice were fed DE-containing diets for all 5 months (prophylactic groups). Terminal plasma DE levels were comparable (~330 ng/ml) in mice fed AIN-93M+DE and HFD+DE. Therapeutic intervention with DE prevented excess body weight gain, marked by no further increase in body fat mass, in HFD-fed mice. DE treatment elicited a selective reduction in micro-, but not macro-vesicular, hepatocellular steatosis in mice with established HFD-induced obesity. In addition, DE treatment prevented progression of liver injury (i.e., serum alanine aminotransferase levels) in HFD-fed mice. HFD-induced hyperglycemia was significantly attenuated in DE-treated mice, suggesting improved insulin sensitivity. DE treatment did not significantly affect these parameters in AIN-93M-fed mice. Analysis of inflammatory cytokines linked to metabolic inflammation revealed a robust increase in plasma KC/Gro, a neutrophil chemokine related to adiposity and insulin resistance, in HFD-fed mice. Notably, both prophylaxis and intervention with DE dramatically reduced plasma KC/Gro levels. Overall, the data suggest that DE can halt the progression of diet-induced obesity and NAFLD in mice fed a HFD. Moreover, the results suggest that thrombin-mediated chemokine induction contributes to HFD induction of obesity and liver disease in mice.