Cardiovascular metabolic profile of long-term dietary and physical exercises intervention on female Long-Evans rats

Abstract Obesity is an increasing burden worldwide1 and it has been associated with pathological cardiac remodeling2. Obese people are twice as likely to develop heart failure (HF) than those with a normal Body Mass Index3. The purpose of this study was to examine long-term metabolic changes in the heart and aorta in response to exercise in a rat model of diet-induced obesity. Ninety-five female Long-Evans rats were divided into two main groups: One group performed exercise (exe) on a treadmill with 10% slope for 30 minutes 4 days a week, while the other group was used as sedentary controls. Each group was further subdivided into three diet groups: control diet (CTRL), high-fat diet (HF), and high-fat, high-sugar diet (HFHS). Dietary and training interventions started from the 5th month of age and were carried out for 8 months, followed by sacrification and organ collection. Heart and aorta were harvested and fixed in formalin for histological analysis or flash-frozen for metabolomic analysis. Pathological cardiac remodeling was assessed by measuring body weight (BW), visceral adipose tissue (VAT), echocardiography, and fibrosis. The heart and aorta were divided into the left ventricle (LV) apex, aortic arch, and descending aorta. Metabolomic analysis was carried out using HILIC chromatography and a triple quadrupole mass spectrometer. We found that hypercaloric diets caused a significant increase in BW and VAT accumulation (HFexe to CTRLexe fold change FC= 1,15, p0,001; HF to CTRL FC=1,11, p0,05) and (HFexe to CTRLexe FC=1,94, p0,001; HF to CTRL FC=2,05, p0,001) respectively for BW and VAT. Whereas exercise only reduced BW but not VAT (CTRL to CTRLexe FC=1,11 p0,05). Echocardiography showed no significant changes in heart function; however, trained rats had significantly larger LV mass compared to the sedentary group of the respective diet (HFexe to HF FC=0,68 p0,01). Finally, trichrome staining showed that physical activity reduced fibrosis (HFexe to HF FC=0,23 p0,001). Metabolomic analysis showed that among the dysregulated metabolites, taurine and choline levels decreased significantly with the hypercaloric diet (HFHSexe to CTRLexe FC= 0,67 p0,001and FC= 0,70 p0,05, respectively. Citrulline, NADP+, glutathione, and S-adenosyl-L-homocysteine levels increased in the caloric diets compared with control in both trained and sedentary groups (All HFHSexe to CTRLexe respectively: FC=1,51 p0,05; FC=1,84 p0,05; FC=1,42 p0,05; FC=2,02 p0,05). In conclusion, dietary intervention in a rat model increased BW and VAT accumulation. Although training was associated with heart hypertrophy, trained rats showed a significantly lower degree of fibrosis than sedentary rats. The diet affected the metabolic profile more than training, despite differences in cardiac remodeling. The altered metabolites fare related to glutathione pathway, DNA methylation as well as NOS activation, highlighting the role of these pathways in cardiac remodeling.