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. 2015 Aug 27;10(8):e0136915.
doi: 10.1371/journal.pone.0136915. eCollection 2015.

CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity

David A Cappel  1 , Louise Lantier  1 , Brian T Palmisano  1 , David H Wasserman  1 , John M Stafford  2
Affiliations

CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity

David A Cappel et al. PLoS One. .

Abstract

Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. CETP expression does not alter weight or adiposity gain on HFD.
(A) Body weight over the course of HFD-feeding. (B) Body composition at baseline and 4-weeks post HFD. n = 5–8 mice per group.
Fig 2
Fig 2. CETP expression improves endurance performance in female mice.
(A) Run duration throughout the course of HFD. (B) Run duration in chow-fed mice before switch to HFD. (C) Run duration after 6 weeks of HFD-feeding. (D) Run distance throughout the course of HFD. (E) Run distance in chow-fed mice before switch to HFD. (F) Run duration after 6 weeks of HFD-feeding. Error bars represent mean ± SEM. n = 5–8 mice per group. † indicates significance by repeated measures ANOVA with Fisher’s least significant difference test. * indicates p<0.05 by unpaired t-test.
Fig 3
Fig 3. CETP expression does not alter VO2Max.
(A) VO2Max in WT and CETP mice throughout the course of HFD. (B) Oxygen consumption in chow-fed mice during the initial exercise study. Solid line indicates beginning of exercise trial. Dashed line indicates median exercise time for both WT and CETP mice. (C) Oxygen consumption in HFD-fed mice during the exercise trial following 4 weeks of HFD. Solid line indicates beginning of exercise trial. Dotted line indicates median exercise time for WT mice. Dashed line indicates median exercise time for CETP mice. Error bars represent mean ± SEM. n = 5–8 mice per group.
Fig 4
Fig 4. CETP expression increases mitochondrial oxidation in female mice.
(A) Oxygen consumption in isolated muscle fibers treated with glutamate/malate mixture to measure total substrate oxidation. (B) Oxygen consumption in isolated muscle fibers treated with palmitoylcarnitine to measure fatty acid oxidation. Data represent mean ± SEM. n = 8–14 muscle fibers per group. * indicates p<0.05 by unpaired t-test.
Fig 5
Fig 5. CETP expression increases mRNA for muscle PGC-1α.
Gene expression in muscle tissue collected immediately following exercise. Data represent mean ± SEM. n = 4 mice per group. * indicates p<0.05 by unpaired t-test.
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