Effectiveness of high cardiorespiratory fitness in cardiometabolic protection in prediabetic rats

Abstract

Background: Caloric restriction and exercise are lifestyle interventions that effectively attenuate cardiometabolic impairment. However, cardioprotective effects of long-term lifestyle interventions and short-term lifestyle interventions followed by weight maintenance in prediabetes have never been compared. High cardiorespiratory fitness (CRF) has been shown to provide protection against prediabetes and cardiovascular diseases, however, the interactions between CRF, prediabetes, caloric restriction, and exercise on cardiometabolic health has never been investigated.

Methods: Seven-week-old male Wistar rats were fed with either a normal diet (ND; n = 6) or a high-fat diet (HFD; n = 30) to induce prediabetes for 12 weeks. Baseline CRF and cardiometabolic parameters were determined at this timepoint. The ND-fed rats were fed continuously with a ND for 16 more weeks. The HFD-fed rats were divided into 5 groups (n = 6/group) to receive one of the following: (1) a HFD without any intervention for 16 weeks, (2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks, (3) 40% caloric restriction for 16 weeks, (4) a HFD plus an exercise training program for 6 weeks followed by a ND without exercise for 10 weeks, or (5) a HFD plus an exercise training program for 16 weeks. At the end of the interventions, CRF and cardiometabolic parameters were re-assessed. Then, all rats were euthanized and heart tissues were collected.

Results: Either short-term caloric restriction or exercise followed by weight maintenance ameliorated cardiometabolic impairment in prediabetes, as indicated by increased insulin sensitivity, improved blood lipid profile, improved mitochondrial function and oxidative phosphorylation, reduced oxidative stress and inflammation, and improved cardiac function. However, these benefits were not as effective as those of either long-term caloric restriction or exercise. Interestingly, high-level baseline CRF was correlated with favorable cardiac and metabolic profiles at follow-up in prediabetic rats, both with and without lifestyle interventions.

Conclusions: Short-term lifestyle modification followed by weight maintenance improves cardiometabolic health in prediabetes. High CRF exerted protection against cardiometabolic impairment in prediabetes, both with and without lifestyle modification. These findings suggest that targeting the enhancement of CRF may contribute to the more effective treatment of prediabetes-induced cardiometabolic impairment.

Keywords: Cardiometabolic protection; Cardiorespiratory fitness; Lifestyle modification; Prediabetes; Weight maintenance.

Fig. 1

The experimental protocol. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 2

Average energy intake (a), Body weight (b), Visceral fat weight (c). n = 5–6 per group. Data are reported as mean ± SEM. *p < 0.05 when compared to ND, ^†p < 0.05 when compared to PDM, ^‡p < 0.05 when compared to PDMCR-SM, ^§p < 0.05 when compared to PDMCR-L, ^‖p < 0.05 when compared to PDMEX-SM. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 3

Fatty acid oxidation rate (a), Carbohydrate oxidation rate (b), Fatty acid/carbohydrate oxidation rate ratio (c). n = 5–6 per group. Data are reported as mean ± SEM. *p < 0.05 when compared to ND, ^†p < 0.05 when compared to PDM, ^‡p < 0.05 when compared to PDMCR-SM, ^§p < 0.05 when compared to PDMCR-L, ^‖p < 0.05 when compared to PDMEX-SM. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 4

%LVEF (a), %LVFS (b), E/A ratio (c), LF/HF ratio (d). n = 5–6 per group. Data are reported as mean ± SEM. *p < 0.05 when compared to ND, ^†p < 0.05 when compared to PDM, ^‡p < 0.05 when compared to PDMCR-SM, ^§p < 0.05 when compared to PDMCR-L, ^‖p < 0.05 when compared to PDMEX-SM. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 5

Cardiac mitochondrial ROS production (a), Cardiac mitochondrial membrane depolarization (b), Cardiac mitochondrial swelling indicated by the normalized absorbance at λ 540 nm (c), Cardiac respiratory control ratio (d), Cardiac OXPHOS protein expression (e). VDAC was used as a housekeeping protein. n = 5–6 per group. Data are reported as mean ± SEM. *p < 0.05 when compared to ND, ^†p < 0.05 when compared to PDM, ^‡p < 0.05 when compared to PDMCR-SM, ^§p < 0.05 when compared to PDMCR-L, ^‖p < 0.05 when compared to PDMEX-SM. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 6

Expression of insulin signaling-related proteins in the heart (a), Expression of mitochondrial biogenesis and metabolism-related proteins in the heart (b), Expression of mitochondrial fusion-related proteins in the heart (c), Expression of mitochondrial fission-related proteins in the heart (d). VDAC was used as a housekeeping protein. n = 5–6 per group. Data are reported as mean ± SEM. *p < 0.05 when compared to ND, ^†p < 0.05 when compared to PDM, ^‡p < 0.05 when compared to PDMCR-SM, ^§p < 0.05 when compared to PDMCR-L, ^‖p < 0.05 when compared to PDMEX-SM. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 7

TUNEL assay representative of cardiac apoptosis from a rat of each group (a), Apoptotic index in the heart (b), Expression of cytosolic/mitochondrial cytochrome protein in the heart (c). n = 5–6 per group. Data are reported as mean ± SEM. *p < 0.05 when compared to ND, ^†p < 0.05 when compared to PDM, ^‡p < 0.05 when compared to PDMCR-SM, ^§p < 0.05 when compared to PDMCR-L, ^‖p < 0.05 when compared to PDMEX-SM. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 8

Cardiac MDA level (a), Expression of TNF-α protein in the heart (b), Expression of SOD2 protein in the heart (c). GAPDH was used as a housekeeping protein. n = 5–6 per group. Data are reported as mean ± SEM. *p < 0.05 when compared to ND, ^†p < 0.05 when compared to PDM, ^‡p < 0.05 when compared to PDMCR-SM, ^§p < 0.05 when compared to PDMCR-L, ^‖p < 0.05 when compared to PDMEX-SM. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise

Fig. 9

The correlation between running distance at week 12 and week 28 (a), Running distance values (b), The correlations between CRF level at baseline (week 12) versus anthropometry and metabolic parameters at follow-up (week 28) within each group of rats (c), The correlations between CRF level at baseline (week 12) and cardiac parameters at follow-up (week 28) within each group of rats (d), TUNEL assay representative of cardiac apoptosis between high-CRF level and low-CRF level rats in each group (e). CRF was reported as running distance. n = 5–6 per group. Data are reported as mean. *p < 0.05. ND: Normal diet; PDM: Prediabetes with no intervention; PDMCR-SM: Prediabetes with short-term caloric restriction followed by weight maintenance; PDMCR-L: Prediabetes with long-term caloric restriction; PDMEX-SM: Prediabetes with short-term exercise followed by weight maintenance; PDMEX-L: Prediabetes with long-term exercise