Plasma and liver lipidomics response to an intervention of rimonabant in ApoE*3Leiden.CETP transgenic mice

Abstract

Background: Lipids are known to play crucial roles in the development of life-style related risk factors such as obesity, dyslipoproteinemia, hypertension and diabetes. The first selective cannabinoid-1 receptor blocker rimonabant, an anorectic anti-obesity drug, was frequently used in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m(2) with associated risk factors such as type II diabetes and dyslipidaemia in the past. Less is known about the impact of this drug on the regulation of lipid metabolism in plasma and liver in the early stage of obesity.

Methodology/principal findings: We designed a four-week parallel controlled intervention on apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) transgenic mice with mild overweight and hypercholesterolemia. A liquid chromatography-linear ion trap-Fourier transform ion cyclotron resonance-mass spectrometric approach was employed to investigate plasma and liver lipid responses to the rimonabant intervention. Rimonabant was found to induce a significant body weight loss (9.4%, p<0.05) and a significant plasma total cholesterol reduction (24%, p<0.05). Six plasma and three liver lipids in ApoE*3Leiden.CETP transgenic mice were detected to most significantly respond to rimonabant treatment. Distinct lipid patterns between the mice were observed for both plasma and liver samples in rimonabant treatment vs. non-treated controls. This study successfully applied, for the first time, systems biology based lipidomics approaches to evaluate treatment effects of rimonabant in the early stage of obesity.

Conclusion: The effects of rimonabant on lipid metabolism and body weight reduction in the early stage obesity were shown to be moderate in ApoE*3Leiden.CETP mice on high-fat diet.

Figure 1. Food intake and body weight.

The 4-week intervention effect of rimonabant on food intake and body weight was evaluated by measuring body weight (per mouse) and food intake (per cage) of the rimonbant and nontreated control mice at day 0, 2, 3, 4, 9, 11, 14, 21 and 28 respectively. (A) Food intake. (B) Body weight. Values are expressed as means ± SD; * p<0.05 vs. the control.

Figure 2. Plasma cholesterol, triacylglycerides, HDL-C and plasma lipoprotein profiles.

Plasma concentrations are shown for TC (A), TG (B) and HDL-C (C) of the rimonabant and nontreated mice at week 0 and 4. Values are shown as means ± SD; * p<0.05 vs. the control. Alterations of Cho (D) and TG (E) as well as PLs (F) in the pooled lipoprotein profiles of the rimonabant treatment group and the controls (t = week 4). Fractions 4–7 represent VLDL; fractions 8–9 represent intermediate-density lipoprotein (IDL); fractions 10–15 represent LDL; fractions 16–23 represent HDL.

Figure 3. Rimonabant does not significantly affect plasma CETP activity.

Effect of rimonabant on plasma CETP was evaluated by CETP protein level (A) and CETP activity (B) in ApoE*3Leiden.CETP mice at t = week 0 and 4 (white bars: the control group; black bars: the rimonabant group). Values are means ± SD. There were no statistically significant changes found in either CETP or CETP activity during the intervention treatment.

Figure 4. Lipidomics reveals differences between non-treated and rimonabant-treated mice for both plasma and liver samples.

Principle component analyses (PCA) of plasma and liver lipidomics data were applied to differentiate the nontreated controls (n = 7) and the animals treated with rimonabant (n = 8) in plasma and liver samples, respectively. PCA biplots for the first two principal components of lipid profiling of plasma samples (A) and liver samples (B). Both PCA models used mean centred plus unit variance scaled data.

Figure 5. Rimonabant significantly decreases the overall responses of plasma lipid classes.

Relative change of the summation of the individually measured lipids in different lipid classes was determined based on plasma and liver lipidomics data of the rimonabant group and the controls (white bars: plasma samples; black bars: liver samples). The summation of the individually measured lipids in each lipid class in the control is set to be 1, * p<0.05 vs. the control.