Abstract
BackgroundObesity is associated with a hypercoagulable state and increased risk for thrombotic cardiovascular events.ObjectiveEstablish the onset and reversibility of the hypercoagulable state during the development and regression of nutritionally-induced obesity in mice, and its relation to transcriptional changes and clearance rates of coagulation factors as well as its relation to changes in metabolic and inflammatory parameters.MethodsMale C57BL/6J mice were fed a low fat (10% kcal as fat; LFD) or high fat diet (45% kcal as fat; HFD) for 2, 4, 8 or 16 weeks. To study the effects of weight loss, mice were fed the HFD for 16 weeks and switched to the LFD for 1, 2 or 4 weeks. For each time point analyses of plasma and hepatic mRNA levels of coagulation factors were performed after overnight fasting, as well as measurements of circulating metabolic and inflammatory parameters. Furthermore, in vivo clearance rates of human factor (F) VII, FVIII and FIX proteins were determined after 2 weeks of HFD-feeding.ResultsHFD feeding gradually increased the body and liver weight, which was accompanied by a significant increase in plasma glucose levels from 8 weeks onwards, while insulin levels were affected after 16 weeks. Besides a transient rise in cytokine levels at 2 weeks after starting the HFD, no significant effect on inflammation markers was present. Increased plasma levels of fibrinogen, FII, FVII, FVIII, FIX, FXI and FXII were observed in mice on a HFD for 2 weeks, which in general persisted throughout the 16 weeks of HFD-feeding. Interestingly, with the exception of FXI the effects on plasma coagulation levels were not paralleled by changes in relative transcript levels in the liver, nor by decreased clearance rates. Switching from HFD to LFD reversed the HFD-induced procoagulant shift in plasma, again not coinciding with transcriptional modulation.ConclusionsChanges in dietary fat content rapidly alter the mouse plasma coagulation profile, thereby preceding plasma metabolic changes, which cannot be explained by changes in relative expression of coagulation factors or decreased clearance rates.
Highlights
The prevalence of obesity in the Western world is rising, which causes a public health problem since obesity affects, amongst others, the development of cardiovascular diseases through its influence on risk factors like hyperlipidemia, hypertension, glucose intolerance and inflammation
Increased plasma levels of fibrinogen, FII, FVII, FVIII, FIX, FXI and FXII were observed in mice on a high fat diet (HFD) for 2 weeks, which in general persisted throughout the 16 weeks of HFD-feeding
Changes in dietary fat content rapidly alter the mouse plasma coagulation profile, thereby preceding plasma metabolic changes, which cannot be explained by changes in relative expression of coagulation factors or decreased clearance rates
Summary
The prevalence of obesity in the Western world is rising, which causes a public health problem since obesity affects, amongst others, the development of cardiovascular diseases through its influence on risk factors like hyperlipidemia, hypertension, glucose intolerance and inflammation. The risk for thrombotic cardiovascular events is even further enhanced by the hypercoagulable state that is associated with obesity, as obese subjects have increased plasma levels of procoagulant factor (F) VII, VIII, XII and fibrinogen, while fibrinolysis is decreased as reflected by increased levels of plasminogen activator inhibitor-1 (PAI-1) [1,2,3]. It has been suggested that almost one-third of all thrombotic events could be prevented by weight loss [8] Taken together, these data indicate that plasma coagulation factors, and the subsequent thrombotic risk, may follow both the unfavorable and favorable changes in body weight gain and loss, respectively. Obesity is associated with a hypercoagulable state and increased risk for thrombotic cardiovascular events.
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