Changes in Dietary Fat Content Rapidly Alters the Mouse Plasma Coagulation Profile without Affecting Relative Transcript Levels of Coagulation Factors

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.

Effects of different diets used in diet-induced obesity models on insulin resistance and vascular dysfunction in C57BL/6 mice

“…This is consistent with previous studies showing that HFD-fed C57BL/6J mice exhibited significantly shorter aPTT and PT than lean mice fed a standard diet 44 . HFD-feeding of C57BL/6J mice results in higher thrombus weight in a thrombosis model 45 and to increased plasma levels of coagulation factors FII, FVII, FVIII, FIX, FXI and FXII 46 . This may be part of the mechanisms underlying the enhanced activity of the individual coagulation factors observed in the present study (Fig.…”

Hemostasis, endothelial stress, inflammation, and the metabolic syndrome

“…For example, Nishimura et al showed that in obese and HFD-fed mice, there is increased platelet-leukocyte interaction and tethering, and blocking the endothelial inflammatory surface marker ICAM1 can normalize these effects [ 113 ]. Cleuren et al showed that HFD feeding leads to a rapid increase of circulating blood clotting factors, and the source of these is the activated endothelium rather than the liver, which is the main source of circulating clotting factors [ 114 ]. In addition, studies interfering with basic activators of blood clotting or platelet ligands have been shown to ameliorate HFD-induced inflammation and insulin resistance, such as mice lacking PAR2, a key target of tissue factor/factor VII mediated coagulation, or mice lacking the PSGL1, a main ligand for P-selectin, a surface protein exposed on activated platelets [ 115 , 116 ].…”

High-fat diet exacerbates SIV pathogenesis and accelerates disease progression

“…HFD induces atherosclerosis (18) by enhancing dyslipidemia and macrophage infiltration in the aorta (18). HFD also alters the coagulation profiles and promotes hypercoagulopathy, by increasing plasma levels of endogenous thrombin and procoagulant factors (e.g., FII, FVII, FVIII, and FXII), or decreased fibrinolysis (19). Hypercoagulability is common in HIV/SIV infections and may contribute to residual immune activation and inflammation (20) even in individuals with ART suppression (2,3).…”