Body composition.

<p>Average weekly food intake during eleven weeks of treatment, body weight at sacrifice, dry lean mass and organ weights (as percentage of dry lean mass). Data are means from n = 7–10 mice per group, ± SEM.</p

Effects of 14 weeks of WBV treatment on the mitochondrial properties in skeletal muscle of young and old mice.

<p>(A) Maximal ADP-stimulated O₂ flux (state 3) and (B) basal O₂ flux (state 4) in isolated skeletal muscle mitochondria oxidizing pyruvate plus malate. (C) Relative mtDNA copy number in skeletal muscle. (D) Maximal ADP-stimulated O₂ flux (state 3) and (E) basal O₂ flux (state 4) in isolated skeletal muscle mitochondria oxidizing palmitoyl-CoA plus L-carnitine plus malate. (F) Citrate synthase (CS) activity in skeletal muscle. (G) Relative protein levels and (H) representative immunoblot images of selected subunits of oxidative phosphorylation pathway complexes I-V and uncoupling protein 3 (UCP3) in isolated skeletal muscle mitochondria. Data are means from n = 6–9 (A-F) or n = 3 (G-H) mice per group; ± SEM. ^ap<0.05, significant effect of age; ^bp<0.05, significant effect of WBV.</p

Effects of 14 weeks of WBV treatment on the mitochondrial properties in livers of young and old mice.

<p>(A) Maximal ADP-stimulated O₂ flux (state 3) and (B) basal O₂ flux (state 4) in isolated liver mitochondria oxidizing pyruvate plus malate. (C) Relative mtDNA copy number in liver. (D) Maximal ADP-stimulated O₂ flux (state 3) and (E) basal O₂ flux (state 4) in isolated liver mitochondria oxidizing palmitoyl-CoA plus L-carnitine plus malate. (F) Citrate synthase (CS) activity in liver. (G) Relative protein levels and (H) representative immunoblot images of selected subunits of oxidative phosphorylation pathway complexes I-V and uncoupling protein 2 (UCP2) in isolated liver mitochondria. Data are means from n = 6–9 (A-F) or n = 3 (G-H) mice per group; ± SEM. ^a p<0.05, significant effect of age. ^bp<0.05, significant effect of WBV.</p

Blood glucose turnover rates after 12–13 weeks of WBV treatment.

<p>(A) Initial (fasting) and (B) steady-state glucose concentrations during stable isotope infusion experiment. (C) Initial (fasting) insulin concentrations. (D) Endogenous glucose production rates (Ra(glc)). (E) Metabolic clearance rates of blood glucose (MCR), calculated as the ratios of total glucose turnover rates and blood glucose concentrations. Data are averages from n = 6–9 mice per group; ± SEM. ^ap<0.05, significant effect of age; ^b p<0.05, significant of WBV.</p

Animal characteristics.

<p>(A) subcutaneous white fat, (B) visceral white fat weights, (C) plasma leptin concentrations, (D) muscle triglyceride (TG) concentrations, (E) liver TG concentrations, (F) plasma TG concentrations, (G) plasma cholesterol concentrations, (H) plasma free fatty acid (FFA) concentrations. Data are averages from n = 7–9 mice per group; ± SEM. ^ap<0.05, significant effect of age, ^bp<0.05, interaction effect between age and WBV treatment, ^cp<0.05, post-hoc treatment effect.</p

Hepatic carbohydrate fluxes <i>in vivo</i> after 12–13 weeks of WBV treatment.

<p>(A) Glycogen phosphorylase (GP) flux. (B) Glycogen balance, calculated by subtracting GP flux from glycogen synthase (GS) flux. (C) Glucose-6-phosphatase (G6P) flux. (D) Glucokinase (GK) flux. (E) GS flux. (F) Total gluconeogenesis (GNG) flux. (G) Hepatic glycogen content. Data are averages from n = 6–9 mice per group; ± SEM. ^ap<0.05, significant effect of age.</p

Energy expenditure and substrate utilization <i>in vivo</i> after nine weeks of WBV treatment.

<p>(A) Average dry lean mass-corrected energy expenditures (EE) and (B) average respiratory quotients (RQ) during light phase, dark phase and 24 hours. (C) Average lipid and carbohydrate oxidation rates per 24 hours. (D) Average oxygen consumption during light phase, dark phase and 24 hours. Data are averages from n = 7–8 mice per group; ± SEM. ^a p<0.05, significant effect of age.</p

Dataset for: Male apoE*3-Leiden.CETP – mice on high-fat high-cholesterol diet exhibit a biphasic dyslipidemic response, mimicking the changes in plasma lipids observed through life in men.

The physiological adaptations resulting in the development of the metabolic syndrome in man occur over a time span of several decades. This combined with the prohibitive financial cost and ethical concerns to measure key metabolic parameters repeatedly in subjects for the major part of their life span, makes that comprehensive longitudinal human data sets are virtually non-existent. While experimental mice are often used, little is known whether this species is in fact an adequate model to better understand the mechanisms that drive the metabolic syndrome in man. We took up the challenge to study the response of male apoE*3-Leiden.CETP mice (with a humanized lipid profile) to a high-fat high-cholesterol diet for six months. Study parameters include body weight, food intake, plasma and liver lipids, hepatic transcriptome, VLDL – triglyceride production and importantly the use of stable isotopes to measure hepatic de novo lipogenesis, gluconeogenesis, and biliary/fecal sterol secretion to assess metabolic fluxes. The key observations include 1) high inter-individual variation, 2) a largely unaffected hepatic transcriptome at 2, 3 and 6 months, 3) a biphasic response curve of the main metabolic features over time, and 4) maximum insulin resistance preceding dyslipidemia. The biphasic response in plasma triglyceride and total cholesterol appears to mimic that of men in cross-sectional studies. Combined, these observations suggest that studies such as these can help to delineate the causes of metabolic derangements in patients suffering from metabolic syndrome

Cecal acetate and propionate increase GLP-1 expression.

<p>(A) Cecal SCFA concentrations after 6h cecal SCFA infusion in mice fed HFD without guar gum for 6 weeks. (B) After 6h cecal SCFA infusion cecal mRNA expression of Ffar2, PYY and GLP-1 were assessed qPCR. (C-D) Plasma PYY and GLP-1 concentrations after 6h cecal SCFA infusion. Values are presented as mean ± SEM for n = 6–8; *p<0.05, ***p<0.001.</p

Guar gum increases colonic GLP-1 expression.

<p>(A) Cecal mRNA expression of PYY and GLP-1 were assessed by qPCR after 12 weeks of diet. (B-C) Plasma PYY and GLP-1 concentrations after 12 weeks of diet. (D) Cecal mRNA expression of Ffar2 was assessed by qPCR after 12 weeks of diet. Values are presented as mean ± SEM for n = 6–8; ***p<0.001.</p