title: Changes in Dietary Fat Content Rapidly Alters the Mouse Plasma Coagulation Profile without Affecting Relative Transcript Levels of Coagulation Factors.
abstract: BACKGROUND
  Obesity is associated with a hypercoagulable state and increased risk for thrombotic cardiovascular events.
  
  
  OBJECTIVE
  Establish 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.
  
  
  METHODS
  Male 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.
  
  
  RESULTS
  HFD 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Audrey C A
authors.initials: AC
authors.lastname: Cleuren
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Vicky T
authors.initials: VT
authors.lastname: Blankevoort
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Daniël
authors.initials: D
authors.lastname: Verhoef
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Pieter H
authors.initials: PH
authors.lastname: Reitsma
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: van Vlijmen
mesh_terms: D000818:Animals; D001779:Blood Coagulation Factors / Q000032:analysis*; D016207:Cytokines / Q000097:blood; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000097:blood* / Q000378:metabolism; D005164:Factor IX / Q000032:analysis; D005167:Factor VII / Q000032:analysis; D005169:Factor VIII / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000209:etiology; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D012313:RNA / Q000302:isolation & purification / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D001779:Blood Coagulation Factors; D016207:Cytokines; D004041:Dietary Fats; D012313:RNA; D005167:Factor VII; D005169:Factor VIII; D005164:Factor IX