Moderate physical activity was able to prevent some of the maladaptive changes associated with chronic HFHC feeding in young rats, including, however it did not prevent an elevation in blood pressure. Non-significant trends in the data showed some improvement in vascular contractile responses to noradrenaline. Electrophysiological function at 50% and 90% of the action potential duration was significantly increased by HFHC feeding, With the HFHC + PA group values not significantly different to the CON tissues. Moderate intensity physical activity in young healthy rats (PA group) produced the typically expected changes of a reduction in systemic inflammation and maintenance of body weight and systolic blood pressure similar to CON values. In contrast, juvenile-adolescent normotensive rats fed a HFHC diet were mildly hyperglycemic, hypertensive and showed increased renal hypertrophy. Hearts from HFHC fed animals showed significantly prolonged action potentials with systemic increased lipid peroxidation as a common mediator of the metabolic syndrome. The presentation and degree of damage was not as large as reported in other studies, which may be due to the younger age of the animal model and the duration of HFHC feeding [32, 36, 37].
In this study, there was no significant gain in body mass in the HFHC group, despite an excess in kilojoules consumed compared to the CON animals. The amount of weight gain in the HFHC group observed in the current study is similar to a study that used a high fat diet over 12 weeks . However, longer feeding periods (16 weeks) elucidated a larger weight gain response in HFHC fed animals . Although not measured in the current study the weight gain may have been in relation to leptin resistance and appetite regulation. Leptin is an adipocyte-derived peptide, the production of which is increased in patients with obesity . A recent study examined a model of diet-induced obesity and the response to leptin in several stages . In the middle-stage (about 8 weeks), food intake reduced when the animal had an increase in leptin production and still retained central leptin sensitivity . The animals seemed to control the rate of excess fat gain by significantly reducing food intake, however, despite the hypophagia, excess fat still accumulated at a reduced rate with apparent gains in energetic efficiency at least partially preventing this regulatory attempt . However, in the later stages (4 months of high-fat feeding), the energy intake of the high-fat fed mice increased by 14.6% over the control fed animals, accompanied by a reduction of central leptin sensitivity . Clearly, the increase in energy consumption of the HFHC diet in this study promoted changes in adipose deposition causing classical indicators of the metabolic syndrome, increased blood glucose and blood pressure, without excessive weight gain in these younger animals.
Although overall body mass was not significantly increased in the HFHC animals, there was a significant increase in retroperitoneal fat pad weight in the HFHC fed animals. This abdominal fat, has been shown to have a direct correlation with insulin resistance, and may be a better indicator of obesity related complications, than overall body mass [25, 40–44]. HFHC has shown to cause adverse cardiovascular changes in rodent models as well as in humans [32, 37, 45]. HFHC feeding in humans, rats and pig models has been shown to cause adverse cardiovascular changes including coronary endothelial dysfunction, vascular oxidative stress, hypertension and cardiomyocyte hypertrophy . Although overall body mass was not decreased in the HFHC + PA animals retroperitoneal and abdominal fat mass was reduced which may offer cardiometabolic benefits despite the lack of overall reduction in body mass. Although the program of physical activity was unable to significantly reduce overall body mass, retroperitoneal and abdominal, fat mass was reduced and clearly conferred cardiometabolic benefits [46, 47]. It seems that overall body weight reduction may not be the most reliable indicator of the beneficial effects of physical activity .
Kidney hypertrophy was observed in the HFHC group, with no other significant changes in other organ masses. In this study, physical activity, was unable to reduce the increase in mass observed in kidney weight, caused by the HFHC diet. With hypertension thought to be a leading cause of renal disease, it is not surprising that many studies have tried to find the mechanism behind this effect. Studies showing that obesity-induced hypertension in dogs is associated with a shift of renal pressure natriuresis  and that fructose-induced metabolic syndrome is also associated with renal disturbances characterized by renal hypertrophy [49, 50], arteriolopathy, glomerular hypertension, and cortical vasoconstriction . The increase in kidney mass may potentially be due to the mild hypertension observed in the HFHC fed group.
Hypertension is one of the hallmarks of the metabolic syndrome and is induced by fructose and HFHC feeding [32, 51]. The animal model of diet-induced obesity elicits an increase in systolic blood pressure in as little as four weeks [52, 53]. In the present study, a significant increase in systolic BP was observed following 8 weeks of the HFHC diet and continued to increase until 12 weeks, similar to other studies [3, 52, 53]. One of the benefits of physical activity is a reduction in blood pressure [54, 55], which was not observed in either of the physical activity groups in this study. This result is in disagreement with other findings . One study showed that 13 weeks of physical activity caused a significant decrease in BP following diet-induced obesity in rats . The length of physical activity treatment (8 weeks) in the current study may not have been long enough to attenuate the change caused by the HFHC diet. The speed and pace used in the current study in normal rats does induce improved left ventricular functional performance over 6–12 weeks period . A significant decrease was not seen in systolic BP, potentially due to it not yet being stabilized, alternatively BP may have stabilized at a level that was not significantly lower. The findings in this study are supported by the isolated vessel studies, which showed no change in aortic dilation responses after physical activity. Other studies showing that cardiovascular damage and steady-state hypertension by diet-induced obesity was achieved only after the 16 weeks of feeding [32, 53].
HFHC feeding showed a trend in decreasing inflammatory cytokine levels both in agreement [40, 44] and contrast to previous studies [21, 32, 37, 42]. These contrasting findings may be related to systemic inflammation as an expression of advanced obesity and insulin resistance which may not be present in animals treated for 12 weeks . However physical activity significantly decreased IL-6 and IL-1 β concentrations compared to the CON and HFHC fed groups. Animal studies have shown that cytokine expression is decreased in a physical activity model, and it was hypothesized that this may occur due to increased utilization of circulating fatty acids . In addition, physical activity can reverse the increased levels of pro-inflammatory cytokine expression correlated to increased body mass, despite continued consumption of a high fat diet . These changes persisted even though the high fat diet/physical activity mice had no significant decrease in body weight compared to the control group . A recent study in a physical activity treated obese rat model found there was reduction in cardiomyocytes with inflammatory infiltrate in comparison to inactive obese rat model .
Oxidative stress originates in the mitochondria from reactive oxygen and reactive nitrogen species and has been linked to most of the key steps in the pathophysiology of CVD . Our results showed a significant increase in this measure in the HFHC animals compared to the CON group. Interestingly, it was also to be significantly increased in our PA group and HFHC + PA group compared to our CON and HFHC group. While the HFHC diet increased lipid peroxidation, physical activity increased lipid peroxidation even further. Physical activity has been shown to induce oxidative stress partially through increased mitochondrial turnover, however with this is an adaptation or up regulation of oxidant defenses [58, 59]. This increase in oxidative stress seen is only an issue when it is in response to other maladaptive processes like diet-induced obesity [25, 60].
The potential for cardiac arrhythmia development was increased in the young HFHC fed rats as demonstrated by a significant prolongation of the cardiac action potential. It has been found that in both obese and control rats that the four major ionic membrane currents responsible for controlling action potential duration are similar . This suggests that prolonged action potential duration seen in HFHC animals was due to a different mechanism. One hypothesized theory is the absence of leptin in these animals on the ventricular sodium calcium exchange current. It has been shown that leptin receptor expression is down regulated in the hearts of obese animals compared to normal fed control animals . Papillary muscles from the high fat diet fed rat hearts showed higher basal and maximum forces but a decreased recovery after a higher workload . The underlying mechanism which links diet-induced obesity to the progression of mild cardiac hypertrophy is unclear . It is hypothesized that obesity promotes pathological cardiac remodeling with left ventricular systolic dysfunction and an increase in myocardial stiffness, which, in turn, is probably related to afterload elevation and cardiac fibrosis . Although physical activity was not able to completely reduce the prolonged action potential duration at both 50% and 90% following chronic HFHC feeding, it was able to significantly attenuate this increase. Changes seen in blood glucose, fat mass and inflammatory signaling were potential factors for this improvement but also improved calcium handling leading to increased cardiomyocyte contractility .
HFHC feeding was shown to cause a decreased response of the right atria to adrenergic stimulation. These changes have been hypothesized to be driven by ionic current changes . Typically, expected findings occurred whereby exercise caused a decrease in heart rate response due to reduction in β-adrenergic receptors in the right atrium . This also occurred during the HFHC + PA group and was a healthy adaptation.
In conclusion, HFHC feeding in young rats induced a mild metabolic syndrome characterized by elevated BP and blood glucose, along with kidney hypertrophy, adipocytokine release, oxidative stress and cardiac action potential prolongation. Changes in vascular and respiratory tissues responses were minimal and linked to the juvenile-adolescent age of the experimental model. Physical activity in the young HFHC fed animals induced improvements in CVD risk by reducing components of the metabolic syndrome including a reduction in lipid peroxidation and cardiac action potential duration, which was believed to be mediated by a reduction in systemic inflammation.