Search

Overactivation of the classical arm of the renin-angiotensin (Ang) system (RAS) occurs during inflammation, oxidative stress and obesity-induced cardiomyopathy. The activation of the protective arm of RAS may act to counterbalance the deleterious effects of the classical RAS. Although aerobic exercise training (AET) shifts the balance of the RAS towards the protective arm, little is known about the molecular adaptations to different volumes of AET. The aim of this study was to evaluate the impact of AET volume on the modulation of RAS, as well as on cardiac biomarkers of oxidative stress and inflammation, in a diet-induced obesity model. Male Wistar rats were fed either control (CON) or high fat (HF) diet for 32 weeks. At week 20, HF group was subdivided into sedentary, low (LEV, 150 min/week) or high (HEV, 300 min/week) exercise volume. After 12 weeks of exercise, body mass gain, systolic blood pressure and heart rate were evaluated, as well as RAS, oxidative stress and inflammation in the heart. Body mass gain, systolic blood pressure and heart rate were higher in HF group when compared with SC group. Both trained groups restored systolic blood pressure and heart rate, but only HEV reduced body mass gain. Regarding the cardiac RAS, the HF group exhibited favoring of the classical arm and both trained groups shifted the balance towards the counterregulatory protective arm. The HF group had higher B1R expression and lower B2R expression than the control group, and B2R expression was reverted in both trained groups. The HF group also presented oxidative stress. The LEV and HEV groups improved the cardiac redox status by reducing Nox 2 and nitrotyrosine expression, but only the LEV group was able to increase the antioxidant defense by increasing Nrf2 signaling. While the HF group presented higher TNF-α, IL-6 and NFκB expression, and lower IL-10 expression, than the SC group, both training protocols improved the inflammatory profile. Although both trained groups improved the deleterious changes related to obesity cardiomyopathy, it is clear that the molecular mechanisms differ between them. Our results suggest that different exercise volumes might reach different molecular targets, and this could be a relevant factor when using exercise to manage obesity. • Obesity increased cardiac inflammation, oxidative stress and ACE/AT1R activation. • 12 weeks of two different exercise volume protocols were tested for its benefits on the heart. • Both training volumes reduced Nox2 expression, nitrosative damage, and inflammation. • Increased Nrf2 signaling was observed with 150 min, but not 300 min of weekly exercise. • Higher exercise volume favored the alternative arm of renin angiotensin system. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model. HF diet led to favoring of the RAS classical arm and increased ER stress through higher expression of the eIF2α pathway. These results could be related to HF diet-associated insulin resistance and upregulation of gluconeogenesis enzymes PEPCK and G6Pase, as well as lipid accumulation through increased lipogenic transcription factor SREBP1c and lower PPARα levels. Enalapril treatment, aerobic exercise training, and the combination of both interventions were able to favor the RAS counterregulatory arm, improve ER stress and decrease lipid accumulation. All interventions were also able to improve insulin resistance, although aerobic exercise training showed more efficiency, reverting glucose intolerance and decreasing the expression of PEPCK. Aerobic exercise training was also the only intervention able to reduce binucleation of hepatocytes and the association with enalapril treatment reverted the increase in hepatocytes with two or more nuclei, which could be suggestive of liver damage associated with the pharmacological treatment. [Display omitted] • Enalapril and aerobic exercise training decrease ACE/ACE2 ratio in obese mice. • RAS counterregulatory arm could be associated to decreased ER stress markers in MAFLD. • Aerobic exercise training better improved liver ER stress markers, metabolism and damage. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model. HF diet led to favoring of the RAS classical arm and increased ER stress through higher expression of the eIF2α pathway. These results could be related to HF diet-associated insulin resistance and upregulation of gluconeogenesis enzymes PEPCK and G6Pase, as well as lipid accumulation through increased lipogenic transcription factor SREBP1c and lower PPARα levels. Enalapril treatment, aerobic exercise training, and the combination of both interventions were able to favor the RAS counterregulatory arm, improve ER stress and decrease lipid accumulation. All interventions were also able to improve insulin resistance, although aerobic exercise training showed more efficiency, reverting glucose intolerance and decreasing the expression of PEPCK. Aerobic exercise training was also the only intervention able to reduce binucleation of hepatocytes and the association with enalapril treatment reverted the increase in hepatocytes with two or more nuclei, which could be suggestive of liver damage associated with the pharmacological treatment. [Display omitted] • Enalapril and aerobic exercise training decrease ACE/ACE2 ratio in obese mice. • RAS counterregulatory arm could be associated to decreased ER stress markers in MAFLD. • Aerobic exercise training better improved liver ER stress markers, metabolism and damage. [ABSTRACT FROM AUTHOR]