Although exercise reduces several cardiovascular risk factors associated with obesity/diabetes, the metabolic effects of exercise on the heart are not well-known. This study was designed to investigate whether high-intensity interval training (HIT) is superior to moderate-intensity training (MIT) in counteracting obesity-induced impairment of left ventricular (LV) mechanoenergetics and function. C57BL/6J mice with diet-induced obesity (DIO mice) displaying a cardiac phenotype with altered substrate utilization and impaired mechanoenergetics were subjected to a sedentary lifestyle or 8–10 weeks of isocaloric HIT or MIT. Although both modes of exercise equally improved aerobic capacity and reduced obesity, only HIT improved glucose tolerance. Hearts from sedentary DIO mice developed concentric LV remodeling with diastolic and systolic dysfunction, which was prevented by both HIT and MIT. Both modes of exercise also normalized LV mechanical efficiency and mechanoenergetics. These changes were associated with altered myocardial substrate utilization and improved mitochondrial capacity and efficiency, as well as reduced oxidative stress, fibrosis, and intracellular matrix metalloproteinase 2 content. As both modes of exercise equally ameliorated the development of diabetic cardiomyopathy by preventing LV remodeling and mechanoenergetic impairment, this study advocates the therapeutic potential of physical activity in obesity-related cardiac disorders.

This study shows that high intensity training is required for induction of changes in cardiac substrate utilization and energetics, which may contribute to the superior effects of high compared with moderate intensity training in terms of increasing aerobic capacity.

Lund J, Hafstad AD, Boardman NT, Rossvoll L, Rolim NP, Ahmed MS, Florholmen G, Attramadal H, Wisløff U, Larsen TS, Aasum E. Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice. Am J Physiol Heart Circ Physiol 308: H823-H829, 2015. First published January 30, 2015; doi:10.1152/ajpheart.00734.2014.-Although exercise training has been demonstrated to have beneficial cardiovascular effects in diabetes, the effect of exercise training on hearts from obese/diabetic models is unclear. In the present study, mice were fed a high-fat diet, which led to obesity, reduced aerobic capacity, development of mild diastolic dysfunction, and impaired glucose tolerance. Following 8 wk on high-fat diet, mice were assigned to 5 weekly high-intensity interval training (HIT) sessions (10 ϫ 4 min at 85-90% of maximum oxygen uptake) or remained sedentary for the next 10 constitutive weeks. HIT increased maximum oxygen uptake by 13%, reduced body weight by 16%, and improved systemic glucose homeostasis. Exercise training was found to normalize diastolic function, attenuate diet-induced changes in myocardial substrate utilization, and dampen cardiac reactive oxygen species content and fibrosis. These changes were accompanied by normalization of obesity-related impairment of mechanical efficiency due to a decrease in work-independent myocardial oxygen consumption. Finally, we found HIT to reduce infarct size by 47% in ex vivo hearts subjected to ischemia-reperfusion. This study therefore demonstrated for the first time that exercise training mediates cardioprotection following ischemia in diet-induced obese mice and that this was associated with oxygen-sparing effects. These findings highlight the importance of optimal myocardial energetics during ischemic stress. cardiac efficiency; myocardial oxygen consumption; mechanoenergetics; high-intensity exercise; diet-induced obesity THERE HAS BEEN a dramatic transition from physical activity to sedentary lifestyle during the last century. This has resulted in an epidemic increase in the prevalence of metabolic syndrome, obesity, and diabetes, all of which increase the risk of developing cardiovascular and metabolic disorders (15, 42). Cardiovascular diseases are the major causes of morbidity and mortality in type 2 diabetic patients (25) who are at higher risk of developing heart failure, angina, acute myocardial infarction, and dying from an acute myocardial infarction (2).Diabetes-related cardiac complications are due to increased coronary artery disease as well as the development of a specific diabetic cardiomyopathy characterized by ventricular dysfunction in the absence of coronary artery disease or hypertension (24). Although the pathogenesis of diabetes/obesity-related cardiomyopathy is multifactorial and complex, decreased cardiac efficiency seems to play an essential role and is an early hallmark of the diabetic heart (5, 9, 22, 36).Physical training is a well-documented measure to reduce the development of obesity/diabetes, as well as an effec...

We showed previously that dietary supplementation with oil from the marine zooplankton Calanus finmarchicus (Calanus oil) attenuates obesity, inflammation, and glucose intolerance in mice. More than 80% of Calanus oil consists of wax esters, i.e., long-chain fatty alcohols linked to long-chain fatty acids. In the present study, we compared the metabolic effects of Calanus oil-derived wax esters (WE) with those of purified eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) ethyl esters (E/D) in a mouse model of diet-induced obesity. C57BL/6J mice received a high-fat diet (HFD; 45% energy from fat). After 7 wk, the diet was supplemented with either 1% (wt:wt) WE or 0.2% (wt:wt) E/D. The amount of EPA + DHA in the E/D diet was matched to the total amount of n-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the WE diet. A third group was given an unsupplemented HFD throughout the entire 27-wk feeding period. WE reduced body weight gain, abdominal fat, and liver triacylglycerol by 21%, 34%, and 52%, respectively, and significantly improved glucose tolerance and aerobic capacity. In abdominal fat depots, WE reduced macrophage infiltration by 74% and downregulated expression of proinflammatory genes (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1), whereas adiponectin expression was significantly upregulated. By comparison, E/D primarily suppressed the expression of proinflammatory genes but had less influence on glucose tolerance than WE. E/D affected obesity parameters, aerobic capacity, or adiponectin expression by <10%. These results show that the wax ester component of Calanus oil can account for the biologic effects shown previously for the crude oil. However, these effects cannot exclusively be ascribed to the content of n-3 PUFAs in the wax ester fraction.

Exercise training is a potent therapeutic approach in obesity and diabetes that exerts protective effects against the development of diabetic cardiomyopathy and ischemic injury. Acute increases in circulating fatty acids (FAs) during an ischemic insult can challenge the heart, since high FA load is considered to have adverse cardiac effects. In the present study, we tested the hypothesis that exercise-induced cardiac effects in diet-induced obese mice are abrogated by an acute high FA load. Diet-induced obese mice were fed a high-fat diet (HFD) for 20 wk. They were exercised using moderate- and/or high-intensity exercise training (MIT and HIT, respectively) for 10 or 3 wk, and isolated perfused hearts from these mice were exposed to a high FA load. Sedentary HFD mice served as controls. Ventricular function and myocardial O consumption were assessed after 10 wk of HIT and MIT, and postischemic functional recovery and infarct size were examined after 3 wk of HIT. In addition to improving aerobic capacity and reducing obesity and insulin resistance, long-term exercise ameliorated the development of diet-induced cardiac dysfunction. This was associated with improved mechanical efficiency because of reduced myocardial oxygen consumption. Although to a lesser extent, 3-wk HIT also increased aerobic capacity and decreased obesity and insulin resistance. HIT also improved postischemic functional recovery and reduced infarct size. Event upon the exposure to a high FA load, short-term exercise induced an oxygen-sparing effect. This study therefore shows that exercise-induced cardioprotective effects are present under hyperlipidemic conditions and highlights the important role of myocardial energetics during ischemic stress. The exercise-induced cardioprotective effects in obese hearts are present under hyperlipidemic conditions, comparable to circulating levels of FA occurring with an ischemic insult. Myocardial oxygen sparing is associated with this effect, despite the general notion that high fat can decrease cardiac efficiency. This highlights the role of myocardial energetics during ischemic stress.

Relatively scarce information is found on the period immediately following physical stress, with special reference to human platelet activity. This, in connection with earlier observations of an increase in platelet release products and hyperaggregability following surgical stress, has initiated the present study. We studied platelet function in eight healthy non-mediated volunteers during and 1 h after cycle exercise of submaximal intensity. ADP-induced platelet aggregability was enhanced in the last minute of exercise followed by a decreased aggregability 1 h after. Adrenaline-induced platelet aggregation showed the same attenuation after exercise but no change during work. The release products beta-thromboglobulin and serotonin in plasma showed significant increases after exercise. This is taken as evidence of an enhanced platelet activity following exercise. A normal stress-response, measured as increase in cyclic AMP in plasma, was observed. In conclusion, platelets are activated following moderate exercise and it seems valid to include the post-exercise period in future studies.

Physical activity is an efficient strategy to delay development of obesity and insulin resistance, and thus the progression of obesity/diabetes-related cardiomyopathy. In support of this, experimental studies using animal models of obesity show that chronic exercise prevents the development of obesity-induced cardiac dysfunction (cardiomyopathy). Whether exercise also improves the tolerance to ischemia-reperfusion in these models is less clear, and may depend on the type of exercise procedure as well as time of initiation. We have previously shown a reduction in ischemic-injury in diet-induced obese mice, when the exercise was started prior to the development of cardiac dysfunction in this model. In the present study, we aimed to explore the effect of exercise on ischemic-tolerance when exercise was initiated after the development obesity-mediated. Male C57BL/6J mice were fed a high-fat diet (HFD) for 20–22 weeks, where they were subjected to high-intensity interval training (HIT) during the last 3 weeks of the feeding period. Sedentary HFD fed and chow fed mice served as controls. Left-ventricular (LV) post-ischemic functional recovery and infarct size were measured in isolated perfused hearts. We also assessed the effect of 3-week HIT on mitochondrial function and myocardial oxygen consumption (MVO2). Sedentary HFD fed mice developed marked obesity and insulin resistance, and demonstrated reduced post-ischemic cardiac functional recovery and increased infarct size. Three weeks of HIT did not induce cardiac hypertrophy and only had a mild effect on obesity and insulin resistance. Despite this, HIT improved post-ischemic LV functional recovery and reduced infarct size. This increase in ischemic-tolerance was accompanied by an improved mitochondrial function as well as reduced MVO2. The present study highlights the beneficial effects of exercise training with regard to improving the ischemic-tolerance in hearts with cardiomyopathy following obesity and insulin resistance. This study also emphasizes the exercise-induced improvement of cardiac energetics and mitochondrial function in obesity/diabetes.

Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.