There is a vast array of evidence supporting exercise with metabolic syndrome. Overall, exercise improves both the cellular components of metabolic syndrome as well as the systemic risk factors that make up metabolic syndrome. As metabolic syndrome begins to gain national attention, the impact of exercise is starting to be known to the general public. In fact, a news station in North Carolina published a segment on a study comparing the effects of exercise on metabolic syndrome. The following description and youtube video summarize the systemic effects and benefits of exercise. Following this summary, the rest of the page describes the cellular effects of exercise and provides a recommendation for exercise in a population of metabolic syndrome.
A study by Johnson et al. evaluated the effects of different levels of exercise on the prevalence of metabolic syndrome in men and women. N = 171 participants (n = 80 women, n = 91 men) completed all portions of the study. They were mildly overweight to obese (BMI of 25 to 35), sedentary adults ages 40 to 65 years old. The participants were randomly assigned to a 6-month control of 1 of 3 eight month exercise training groups:
- low amount/moderate intensity [caloric equivalent of approximately 19 km (12 miles)/week at 40–55% of peak oxygen consumption]
- low amount/vigorous intensity [caloric equivalent of approximately 19 km (12 miles)/week at 65–80% peak oxygen consumption]
- high amount/vigorous intensity [caloric equivalent of approximately 32 km (20 miles)/week at 65–80% peak oxygen consumption]
The prescribed intensity was based on an initial maximal cardiopulmonary exercise test. Prior to initiation of the exercise training protocols, a 2-3 month ramp period was used to slowly increase the participants exercise level up to the assigned intensity. Approved modes of exercise included the use of treadmills, elliptical machines and cycle ergometers. All participants were instructed to maintain their current dietary intake throughout the study.
The following measurements were taken at pre-testing and post-testing: height and weight, waist circumference, blood pressure, lipid levels, insulin sensitivity, and presence of metabolic syndrome using the diagnostic criteria defined by NCEP ATPIII. The researchers found that, compared to the inactive controls, moderate intensity exercise – at an amount calorically equivalent to walking approximately 17 km (10 to 11 miles) over an average of 170 minutes per week – resulted in a significant improvement in the prevalence of metabolic syndrome in both men and women. This study also found that for the group that did a higher amount of more vigorous exercise – an energy expenditure calorically equivalent to approximately 28 km (17 miles) of jogging over 170 minutes per week – greater and more widespread benefits were realized for both men and women.
Video 1. Summary of Study by Johnson et al.
Table of Contents
In regard to metabolic syndrome, all fat is not created equal. That is, that the NCEP ATPIII, WHO and IDF each list central obesity as part of their criteria for metabolic syndrome. The effects of this dysfunctional fat distribution are wide spread and affect many cellular functions. Exercise can have a positive effect on this aspect of metabolic syndrome and this will be highlighted by examining several scientific studies.
Blair and colleagues first suggested that physical activity is associated with reduced risk of disease, including metabolic syndrome, in the “fat and fit” population, that is, patients who are overweight but still physically active.  One study suggests that this may be due, at least in part, to differences in visceral adipose tissue. This study compared four groups of men that differed in both weight and activity levels: “slim and fit, slim and unfit, fat and fit, and fat and unfit.” Researchers measured both overall body fat and visceral fat and compared each group to their fit/unfit counterpart. For the obese men, total body fat did not differ between the fit and unfit groups, however, the fit group had a significantly decreased amount of visceral adipose tissue. Similar results occurred in the two slim groups, with the fit and slim individuals having less visceral fat than the slim and unfit group. This study highlights the positive effects of physical activity regardless of body weight.
Fortunately, exercise can be an effective intervention in the treatment of visceral adipose tissue. One study investigated the application of an exercise intervention without calorie restriction and without the goal of weight loss. The study included 27 men with and without type 2 diabetes, with 17 of the patients being clinically obese. All patients performed a 13-week intervention consisting of treadmill walking for 60 minutes, 5 times per week at approximately 60% of their individual VO2 max. Subjects were told to maintain their current diet in order to prevent weight loss. At the end of the intervention, the subjects had significantly reduced their waist circumference without losing any weight. The percentage of visceral fat was significantly reduced (~17%) among those who were considered to be obese. The fact that total body fat reduction was only 6% suggests that visceral adipose tissue is affected by exercise greater than subcutaneous adipose tissue. This trend was also seen in another study with post-menopausal women. With only moderate weight loss seen after a 12-month intervention, a considerable amount of intra-abdominal fat loss was seen. This trend is explained by Lee, stating that visceral adipocytes are more sensitive to the lipolytic effects of increased catecholamines from exercise when compared to subcutaneous adipose tissue.
While exercise is good for reducing central obesity, the type of exercise can determine how beneficial it is. One study looked at the differences in exercise intensity in reducing abdominal/visceral fat in female patients with metabolic syndrome. The study found that women partaking in high intensity exercise training (RPE = 15-17) had significantly greater reductions in abdominal fat when compared to the low intensity group (RPE = 10-12). It is important to state that these two interventions were matched to obtain equal caloric expenditures. This article states that the difference between the two interventions is likely due to the high intensity intervention’s increased ability to induce the secretion of lipolytic hormones; this results in greater post-exercise energy expenditure and fat oxidation, favoring a greater negative energy balance.
Number of Adipocytes
Spalding et al analyzed the dynamics of fat cell turnover in humans. They found a positive correlation between fat mass and fat cell volume in both subcutaneous fat and in visceral fat. To determine whether adipocyte number changes during adulthood, they compared total adipocyte number in 687 adult individuals to previously reported data for children and adolescents. They found that the total adipocyte number increased at two distinct points: (1) in early childhood and (2) again during puberty/adolescence, but this number leveled off and remained constant in adulthood in both lean and obese individuals. Even during extreme condition of weight loss following bariatric surgery, fat cell volume decreased significantly but adipocyte number remained relatively constant. They hypothesized and subsequently determined that adipocytes are generated at a rate near equivalent to adipocyte death, and found that adipocyte death occurred at approximately 8.4% per year with half of the adipocytes replaced every 8.3 years, regardless of BMI or age. To explain the differences in adipocytes between obese and lean individuals, they found that the rate of turnover is near equivalent, but that the mechanistic make-up of the adipocyte cell is different (leptin deficiency) which likely increases appetite and lowers energy expenditure. This explains why obese individuals have difficulties maintaining weight loss; despite similar turnover rates– obese individuals are predisposed from childhood and adolescence to have a higher amount of fat cells AND those cells contain less leptin increasing their appetite and decreasing energy expenditure.
A 4 week exercise program of 60 minutes of biking or running at least 3 days a week in subjects with a recent diagnosis of impaired glucose tolerance or type II diabetes resulted in approximately two thirds having significantly increased glucose disposal rate, which suggests improved insulin sensitivity after training.
In a 12 month randomized control exercise study, independent of weight loss, the effects of different modes of exercise to reduce insulin sensitivity and decreased c-reactive protein (CRP) levels were tested on subjects with diabetes and metabolic syndrome. Independent aerobic exercise, supervised aerobic exercise and supervised aerobic plus resistance training were compared to sedentary controls. The exercise intervention in this study consisted of 60 minutes of exercise 2 days a week at an intensity of 70-80% of VO2max for the supervised aerobic activity group. Those in the supervised combined exercise group completed 40 minutes of aerobic exercise at 70-80% of VO2max and 20 minutes of resistance exercise. Resistance exercises used were chest press, lat pulldown, squat and abdominal exercise. The instructions to the independent exercise group were not clearly explained. All groups were found to have decreased A1C numbers and amounts of CRP after the study, along with significant reductions in inflammatory markers in both the supervised groups. This study found that the most effective mode of exercise was high intensity mixed aerobic and resistance training to improve insulin sensitivity, decrease CRP levels and reduce inflammatory biomarkers (leptin, resistin, IL-1B, IL-6, TNF-α and INF-γ). 
Davidson et. al assessed the effectiveness of different exercise modes on insulin sensitivity and abdominal obesity in a 6 month randomized control trials. Subjects included men and women between 60-80 years with abdominal obesity, at least 102 cm in men and 88 cm in women. The study compared resistance and aerobic exercise both independently and combine against controls. Exercise interventions in this study consisted of aerobic exercise performed 5 days a week for 30 minutes at 60-75% of VO2max, resistance exercise 3 days a week for about 20 minutes, and combine exercise performed 3 days a week and included 30 minutes of aerobic exercise at 60-75% of VO2max and 20 minutes of resistance training. Resistance training in this study included: chest press, shoulder raise, shoulder flexion, leg extension, leg flexion, triceps extension, biceps curl, abdominal crunches, and modified pushups. The combination of resistance and aerobic exercise was found to be superior in reducing both adipose tissue and insulin sensitivity. All three exercise groups had reduced amounts of adipose tissue at the end of the study, but only groups were aerobic exercise was performed showed any improvements in insulin sensitivity. 
The effect of exercise for weight loss versus caloric restriction on peripheral and hepatic insulin sensitivity in obesity was studied in a randomized control trial by Coker et. al. Subjects in this study were both men and women, between the age of 50-80 years with a BMI between 26 and 40. Subjects were randomized into one of four groups: exercise training without weight loss, exercise training with weight loss, caloric restriction with weight loss and controls. Exercise included working out on a cycle ergometer at 50% of VO2max for a duration that allowed them to burn 2500 k/cal per week. After the 12 week intervention, the exercise for weight loss showed the greatest improvements in both peripheral and hepatic insulin sensitivity. This group also had significant decreases in subcutaneous and visceral adipose tissue after the intervention period. 
Another study that looked at exercise for weight loss versus caloric restriction for weight loss on the effects of insulin sensitivity and glucose tolerance used a 12 month randomized control trial in subjects that were either overweight or obese.  Subjects were randomized into exercise group, caloric restriction or controls. No specific exercise intervention was used in this study. Participants worked out at a level that provided either a 16% or 20% of their total daily energy expenditure while using heart rate monitors that stored information to calculate energy expenditure. The participants were allowed to complete workouts independently or supervised. The study also looked that the effects of the intervention on levels of adiponectin, cortisol, free fatty acids and TNF-α. At the end of the intervention period, the study found that both experimental groups produced similar improvements in insulin sensitivity and glucose tolerance. Also there was not a significant difference between levels of adiponectin, cortisol, free fatty acids and TNF-α improvements between the two groups. One method was not found to be superior to the other in this study for improving insulin sensitivity and glucose tolerance. 
In a 12 week randomized control trial comparing the effects of exercise alone versus exercise with caloric restriction on risk factors for cardiovascular disease and the criteria that defines metabolic syndrome found that exercise alone showed improvements in both.  Subjects in this study were between the ages of 55-65 with a BMI between 30-40. The exercise intervention used consisted of 50-60 minutes of exercise 5 days a week on either a treadmill or cycle ergometer. At least 75% of energy was expended on the treadmill. Exercise intensity was at a level of 60-65% of maximal heart rate for the first for weeks and then 80-85% of maximal heart rate thereafter. Both groups showed improvements in body composition, insulin sensitivity, blood pressure and lipid profile. Exercise with caloric restriction showed a more significant reduction in weight loss, but this did not translate to better improvements in the clinical markers of metabolic syndrome. 
Another way that insulin sensitivity is improved by exercise includes altering GLUT-4 expression. In a study of obese type 2 diabetic subjects, a short term exercise program was used to determine the changes to insulin sensitivity and specifically the amount of GLUT-4.  In this study 8 subjects who were obese and had type 2 diabetes were compared to 7 weight matched obese non-diabetic subjects. Exercise intervention consisted of 60 minutes of exercise on a stationary bicycle ergometer at 75% of VO2max for 7 consecutive days. The study found that subjects had a lower blood glucose level, increased P13K pathway activity, and an increased amount of GLUT-4. The improvement of GLUT-4 expression in this study showed an 87% increase in the amount of the protein in just seven days of intervention. 
The studies on exercise effects on insulin sensitivity show that there an improved response to insulin following exercise. The research shows that moderate to high intensity exercise is recommended to produce the maximal improvement to insulin sensitivity. It is also recommended that patient's perform a mixed workout of both aerobic and resistance training to see the most effects at the cellular level. Another conclusion from these studies suggests that caloric restriction is not necessary to improve insulin sensitivity and that exercise alone produces the same if not better results.
The following table contains information about recent animal and human studies looking at the effects of exercise on cytokines associated with metabolic syndrome including the inflammatory cytokines (TNF-α, IL-6, CRP), adiponectin, and various other cytokines.
Table 1. Summary of Exercise Effects on Cytokines
|Subjects||Intervention||Biomarkers Measured||Effects of Intervention||Limitations|
|Obese Zucker Rats (Animal Metabolic Syndrome Model) assigned to either acute exercise group or habitual exercise group, Lean Zucker rats used as a reference.||Acute exercise (AE) group or habitual exercise (HE) group. AE: 1 session of treadmill running for 25-35 minutes with speed at 35cm/s HE: treadmill running 5 days/week for 14 weeks, 35 minute sessions with treadmill speed at 35 cm/s.||TNF-α and IL-6 released from adipocytes macrophages||AE: Increased spontaneous release of TNF-α and decreased spontaneous release of IL-6 in sedentary rats. HE: Improved regulation of TNF-α and IL-6 in exercise-adapted obese rats, approaching behavior of the lean healthy rats.||None Noted|
|Inclusion Criteria: Men with metabolic syndrome (N=32), ages 20-75 years, physically inactive (<30 min of physical activity/day), presence of central obesity. Individuals with known CVD were excluded.||Sedentary Control (SC), Exercise Only (EO), Pravastatin Only (PO), Pravastatin + Exercise (PE). Exercise Protocol: 45-60 minutes of aerobic exercise (walking/jogging on treadmill) with resistance training, 3 days/week||Circulating TNF-α and adiponectin levels in blood||TNF-α levels were significantly decreased in exercise groups compared to SC. No significant change seen in adiponectin levels.||Small sample size, no female representation in sample|
|Men (n=149) and postmenopausal women (n=125) with elevated LDL cholesterol and low HDL cholesterol.||Control, Diet Only (DO), Physical Activity (PA), Diet+PA (DP). Control: No intervention. Diet Protocol: reduced total fat, saturated fat, and cholesterol intake. PA Protocol: 45-60 minutes at 60%-85% maximal heart rate, 3x/week for 12 months||Plasma CRP levels||Significant change in women's CRP levels in DP group compared to control, DO and PA groups. No significant change in men’s CRP levels seen across all groups.||None Noted|
|Adults with metabolic syndrome (N=335) in Northwestern Italy.||Control or Intervention. All participants received general information with emphasis on healthy lifestyle from physicians. Intervention: Individualized prescription of diet, exercise (moderate-intensity activity for at least 150 minutes/week) and behavioral modifications lasting for 12 months.||Plasma CRP levels||Significant reduction in CRP values seen in intervention group compared to control group.||None Noted|
|Males (n=10) and females (n=4) with metabolic syndrome, average age of 62.9 years.||Exercise Intervention: All subjects participated in a 3 week exercise program consisting of daily exercise lasting 3 hours at 40%-60% of their calculated heart rate max. This was followed by a 6 month home exercise program with instructions to continue the same exercise program used in the first 3 weeks. Diet Intervention: All subjects received a balanced diet corresponding to a 500 Kcal deficit vs. their daily energy expenditure.||CRP, TNF-α, and IL-6 levels in the blood||Significant reduction in TNF-α and CRP levels. No change seen in IL-6 levels.||No control group used, no separation between exercise and diet intervention effects possible, poor compliance seen in participants once moved to a home exercise program.|
|Obese women (n=16), n=8 with impaired glucose tolerance and n=8 without impaired glucose tolerance.||12-week exercise program on a bicycle ergometer at 70% maximal heart rate for 30 minutes, 5 days/week||Plasma TNF-α, sTNFR1 and sTNFR2 levels, insulin sensitivity||Significant decreases seen in TNF-α and sTNFR2 levels but not in sTNFR1 levels. Insulin sensitivity was significantly increased, indicating a decrease in the systemic low-grade inflammation seen in metabolic syndrome with a corresponding increase in insulin sensitivity.||None Noted|
|N=3,075 black and white men and women ages 70-79||The participants’ current activity level was evaluated through interviewer-assisted questionnaires; activity levels were broken down into 3 groups: 0 min/wk of exercise, 1-180 min/wk of exercise and >180 min/wk of exercise.||CRP, IL-6, TNF-α, BMI||BMI, TNF-α, IL-6 and CRP levels were lowest in those that exercised >180 min/wk. This seemed to be correlated with a decreased rate of hypertension, diabetes mellitus, peripheral vascular disease, cerebrovascular disease and respiratory disease.||Cross-sectional study does not allow for inference of a cause-and-effect relationship.|
|82 subjects with type II diabetes and metabolic syndrome between 40-75 y.o, BMI 27-40 kg/m2 ||12 month intervention Sedentary control(SC), counseling for low-intensity aerobic exercise(LI), Supervised aerobic program twice per week for 60 min. at 70-80% VO2max (AE), High-intensity mixed exercise: 40 min aerobic at 70-80% VO2max and 20 min resistance exercise at 80% 1RM (HI)||CRP, leptin, resistin, adiponectin IL-1β, IL-6, TNF-α, IFN-۳||Change from baseline to post-intervention: HI showed the greatest change in adipocytes with CRP decreased 54%, leptin decreased 47%, resistin decreased 22%, adiponectin 38%, IL-1β decreased 41%, IL-6 decreased 59%, TNF-α decreased 44%, IFN-۳ decreased by 18%. To a lesser extent changes were seen with LI and AE: LI- CRP ↓’d 12%, AE- CRP decreased 28%, leptin decreased 27%, resistin decreased 14%, adiponectin increased 36%, IL-6 decreased 41%||None noted|
|79 obese physically inactive Caucasian males and females from 18-45 y.o. ||12 week intervention study. Exercise only group (EXO)- supervised aerobic exercise 3 times per week 60-75 min. (intensity not reported). Hypocaloric diet only group (DIO)- a liquid VLED of 600 and 800 kcal/d for 8 wk followed by a weight maintenance diet for 4 wk. Hypocaloric diet and exercise (DEX)- combination of both the diet and exercise plans||adiponectin, plasma lipids, glucose, insulin, AdipoR1 and AdipoR2 in adipose tissue (AT) and skeletal muscle (SM)||In the DIO group, total adiponectin after 12wk was significantly increased by 19%. In the DEX group, total adiponectin was significantly increased by 20%. In the EXO group, total adiponectin was not increased. The expression of AdipoRs in AT was significantly increased after the 12-wk intervention in all three groups (100–120% increase as compared with baseline). The expression of AdipoRs in SM was increased significantly only by EXO and DEX. EXO group improved their VO2max by18%, their body weight by 3.5% and waist circumference by 5.3; however these anthropometric changes were much smaller than changes in the DIO and DEX groups.||It is not known if increased gene expression reflects increased receptor protein. Comparison of results of DIO ad DEX with EXO could underestimate the effects of exercise because of the greater reduction in weight loss and body fat in DIO and DEX groups.|
|21 obese adolescent boys (13.1±0.7 years) BMI >97th percentile by French standards||During the 2 month study subjects were divided into energy restriction group (R), exercise training group (E), and energy restriction⁄exercise training group (RE). R/RE diets were prescribed by a dietician to be 500 kcal per day lower than their normal dietary consumption reported in detailed food diaries. E/RE exercise program consisted of 90 minute sessions 4xwk of moderate intensity at a HR corresponding with their calculated maximum lipid oxidation point (Lipoxmax). Exercise consisted of warm-up, running, jumping, and ball games with HR monitor continuously on.||Plasma insulin, adiponectin, leptin, and resistin, . Insulin resistance measure with homeostasis model assessment (HOMA-IR); Lipoxmax||Plasma adiponectin level increased significantly in R (+39.1%,), E (+34.8%) and RE (+73.7%) groups. Plasma leptin decreased in R (17.6%), E (16.8) and RE (38.8%). Plasma resistin levels increased significantly in E and RE groups only (+28.3 and +29.8%). Plasma insulin levels decreased significantly in E and RE groups only (37.7 and 41.5%). Also, HOMA-IR values decreased significantly in the same groups (35.7 and 51.1%). Lipoxmax was significantly increased in E and RE groups (+39.4 and +74.4%), but not R. BMI, fat mass, waist and hip circumferences, and waist /height ratio decreased significantly in both R and RE, but no significant changes were found in E.||No female representation, small sample size|
|29 women (66.5 ±9.5 years) with metabolic syndrome were randomly assigned to the therapeutic lifestyle management (TLM) intervention group (n=16) or control group (n=13).||The intervention was provided in 12 sessions (3xwk) and consisted of health screening (blood pressure and body weight check), diet instruction, 30 minutes of education, 60 minutes of exercise, and 20 minutes of health counseling. Recorded video was used for exercise which consisted of stretching, strength training with therabands, aerobic dance, and warm-up and cool-down exercises. A home based walking program with pedometers was also given. Supervised and home exercise was calculated to consume 500 kcal. They were instructed to decrease daily caloric intake by 300 kcal. Control group was to maintain normal lifestyle.||MCP-1, RBP-4, fasting glucose, fasting insulin, and homeostasis model assessment (HOMA)||MCP-1 was significantly reduced in the TLM group (5.17%). RBP-4 in both groups decreased but not significantly. Fasting insulin was reduced in the TLM group (14.8%) and HOMA was also significantly reduced in this group (28.6%). Fasting glucose did not exhibit a significant group-by-time interaction||Small sample size, longer follow-up period is needed to verify the impact of TLM, no male representation|
|Male C57BL/6N mice: A mouse model of diet induced obesity and insulin resistance.||Mice were randomly assigned to one of the 6 groups (n = 6 for each group): low-fat diet (LC, 10% calories from fat, 20% calories from protein, 70% calories from carbohydrate), low-fat diet with 30% calorie restriction (LR), high-fat diet (HC, 60% calories from fat), high-fat diet with 30% calorie restriction (HR), high-fat diet with voluntary running exercise (HE), and high-fat diet with a combination of 30% calorie restriction and voluntary exercise (HRE) Mice in HE group were in cages equipped with locked running wheels for 3 days for acclimatization followed by voluntary running (unlocking the wheels) for 8 weeks.||Plasma insulin, RBP-4,leptin, resistin, and Osteopontin (OPN), TNF-α, MCP-1 and IL-6 mRNAs||Calorie restriction (CR) and endurance exercise each significantly reduced serum RBP-4, leptin, and resistin levels. OPN, TNF-α, MCP-1 and IL-6 mRNAs in white adipose tissues were significantly up-regulated (2-8 fold) by high-fat diet feeding. Endurance exercise significantly reduced their levels. When CR was combined with endurance exercise, MCP-1 and IL-6 mRNAs were further reduced.||None noted|
|Twelve obese adolescent subjects consisted of seven females and five males with a mean age of 15.3 ± 0.5 years. BMI 31.8 ± 5.2||32 week long exercise intervention that met 3 times per week for approximately 1 hour. Session consisted of a 5 minute warm-up of light stretching, 45 minutes of aerobic training at 60-85% VO2max and 5-10 minutes of cool down. Subjects chose to exercise on treadmill, Stairmaster, elliptical trainer, rowing machine, stationary cycle, Dance Dance Revolution, or outdoors play activity.||Glucose, insulin, total cholesterol, HDL cholesterol, triglycerides, leptin, resistin, adiponectin, active ghrelin, and total peptid YY (PYY)||The only hormones to reach significance in change were PYY (28%) and resistin (8%). Triglyceride concentration was decreased 23% but concentrations of total cholesterol, HDL cholesterol, and LDL cholesterol did not change. leptin, adiponectin, and active ghrelin, concentrations did not change. Also, weight, waist circumference, and BMI did not change.||No control group, small sample size|
|188 males with a mean age of 45.1_2.51 years and baseline values for insulin, both fasting and after glucose load, were in the upper normal range, which is indicative of prediabetes. BMI= 28.6 ±3.43 Randomly allocated to the diet (n =45), exercise (n =48), combined diet and exercise (n = 58), or control (n =37) group.||12 month long study. Individualized dietary counseling was provided to subjects in the diet and the combined diet and exercise groups at the start of the study, 3 months, and 9 months. Supervised endurance exercise such as aerobics, circuit training, and fast walking or jogging were done 3 times/wk for 60 min.||adiponectin, leptin, IL-6 and IL-8, TNF-α, MCP-1, hepatocyte growth factor, nerve growth factor, CRP, and resistin.||leptin decreased by 5% in the exercise group and by 24% in the diet and exercise group. A significant positive effect of 28% of diet intervention on adiponectin was observed. Waist to hips ratio correlated significantly with leptin, IL-8, TNF-α, and CRP.||No female representation|
Overall, high intensity exercise has the greatest positive effect on cytokine levels;[9,28] however moderate intensity exercise also showed significant effects on cytokine regulation[17,22,23,18]. Low intensity exercise alone had a much smaller effect on cytokine levels.[24,19]
Studies finding strong results in the high intensity[9,17,20] category utilized 120-180 minutes of exercise per week, whereas the moderate intensity exercise studies[22,23,18] required 150-360 minutes of exercise per week. Habitual exercise over a period of several weeks is needed to see improved regulation of cytokines. Studies where diet was added to the exercise protocol resulted in greater regulation of cytokines.[19,23,24,25] It is clear that exercise and diet changes need to become a part of a metabolic syndrome patient's lifestyle.[24,27]
Regular exercise protects against diseases associated with a chronic, systemic, low-grade inflammation like metabolic syndrome. Although the exact mechanism is not yet known, it is suggested that IL-6 has an anti-inflammatory effect as a myokine (cytokine released from muscle tissue) when released from working muscle by inhibiting the expression of TNF-α and through the stimulation of anti-inflammatory cytokines (IL-1ra and IL-10).[29, 30] This is suggested to be the leading factor in the overall anti-inflammatory effect of exercise. During an acute bout of exercise, IL-6 is the first cytokine to be found in elevated levels in the blood. The possibility exists that, with regular exercise, the anti-inflammatory effects of an acute bout of exercise will protect against chronic systemic low-grade inflammation and thereby offer protection against insulin resistance and the development of atherosclerosis, but such a link between the acute effects of exercise and the long-term benefits has not yet been proven.
As a review, the dyslipidemia profile associated with metabolic syndrome includes a combination of low levels of high-density lipoproteins (HDL), high levels of small, low-density lipoproteins (LDL), and hypertriglyceridaemia, which is sometimes labeled the ‘lipid triad’.  This combination is a strong indicator of cardiovascular risk, and has gained attention in the literature.
Kraus et al  conducted a randomized trial to determine the physiological effects of specific, well-defined amounts and intensities of exercise on risk factors for cardiovascular disease. They collected a convenience sample 84 subjects that were sedentary, overweight or mildly obese, and had dyslipidemia. They split the sample into three groups:
- High amount - high intensity = caloric equivalent of jogging approximately 20 miles per week at 65-80% of peak oxygen consumption
- Low amount – high intensity = caloric equivalent of jogging approximately 12 miles per week at 65-80% of peak oxygen consumption
- Low amount – moderate intensity = caloric equivalent of walking approximately 12 miles per week at 40-55% of peak oxygen consumption
There was an initial period of 2-3 months during which the amount and intensity of exercise were gradually increased, followed by 6 months at the above-mentioned exercise prescription. There was also a control group of 27 subjects that completed no exercise. Overall, the amount and intensity of exercise had a direct correlation with improvement in lipid profile when compared to the control group. The high amount – high intensity group had the most significant changes with decreases in concentration and size of LDL and small LDL particles, increases in HDL concentration, and decrease in triglyceride concentration. The two lower amount groups also demonstrated improvements in lipid profile when compared to the control group, but not to as great an extent as the high amount group. A key point to this study is that these changes occurred in the absence of clinically significant weight loss. Another benefit to this study is that it determined a caloric equivalent of 17-18 miles per week and an intensity equivalent to that of jogging at a moderate pace could induce the changes in lipid profile mentioned above. 
Slentz et al took the results of Kraus et al a step further to analyze the effects of detraining on lipoproteins. They aimed to learn whether the beneficial lipid and lipoprotein effects of an aerobic training program last after ending the exercise and whether exercise training intensity or amount impact the duration of benefits. This study utilized the same group of subjects detailed above, and took obtained plasma at baseline, 24 hour, 5 days, and 15 days after exercise cessation. The following results were found:
- In regards to HDL particles (HDL-C, large HDL, and HDL size) the beneficial effects found at 24 hours appeared to stay the same at 5 and 15 days after exercise cessation. The high-amount – high intensity group had the greatest benefits but all three groups demonstrated a trend toward improvement. This may be clinically important as HDL-C is considered to have anti-inflammatory, antioxidative, antiaggregatory, anticoagulant, and profibrinolytic activities.
- In regards to total TGs and VLDL-TG, the moderate-intensity training group had reduced values at 24 hours after exercise by twice the amount as the high-intensity groups. Additionally, the moderate-intensity training group was the only group to have sustained benefits in TGs and VLDL-TG.
- Sustained physical inactivity resulted in statistically significant increases in LDL particle number, small dense LDL, and LDL-C and significant decreases in LDL particle size (creating the small LDLs associated with metabolic syndrome). This combination increases the risk of cardiovascular disease.
Additionally, a few other articles analyzed exercise effects on individuals with and without metabolic syndrome
Table 2: Summary of Exercise Effects on Lipid Profile
|Subjects||Intervention||Dyslipidemia Biomarkers Measured||Effects of Intervention||Limitations|
|Males (n=10) and females (n=4) with metabolic syndrome, average age of 62.9 years.||Exercise Intervention: All subjects participated in a 3 week exercise program consisting of daily exercise lasting 3 hours at 40%-60% of their calculated heart rate max. This was followed by a 6 month home exercise program with instructions to continue the same exercise program used in the first 3 weeks. Diet Intervention: All subjects received a balanced diet corresponding to a 500 Kcal deficit vs. their daily energy expenditure.||Triglycerides, total cholesterol, HDL levels, and LDL levels were assessed.||Significant increase in HDL levels and significant decrease in total cholesterol and LDL levels. A trend showing a decrease in triglycerides that remained low at 6-month follow-up but was not significant.||No control group used, no separation between exercise and diet intervention effects possible, poor compliance seen in participants once moved to a home exercise program.|
|Males (n=51) and females (n=53) with metabolic syndrome, average age of 63.0 years.||Exercise Intervention: All subjects participated in a 6 month (3 days per week) exercise program consisting of stretching, resistance training (10-15 minutes), and aerobic exercise (45 minutes). Resistance training included 7 exercises up to 15 repetitions. Aerobic training included treadmill, stationary cycle, or stair stepper and target HR was 60-90& of HRmax.Diet Intervention: All subjects were asked to maintain normal caloric intake.||Total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides||Significant increase in HDL cholesterol (p=0.01) and trend toward decreased VLDL cholesterol (p=0.07) Additionally, VLDL and triglyceride improvements showed significant correlation to decreases in BMI, body weight, total abdominal fat, abdominal subcutaneous fat, % body fat, and % lean mass.||Controls were volunteers, and thus may have made lifestyle changes independently of the study as volunteers are generally motivated individuals.|
|Obese males (n=24), average BMI of 30.7 kg/m2, average age of 49.4 years. ]||Exercise Intervention: All subjects participated in 12-week exercise program consisting of stretching and aerobic exercise (60-70% of max HR; 60 min/day, 3 days/wk).Diet Intervention: All subjects were asked not to modify their dietary intake.||Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides||Significant reduction in total cholesterol, triglycerides, and LDL cholesterol.||No control group and small sample size.|
|Older obese adults with metabolic syndrome (n=24; 15 females, 9 males), average BMI of 34.3 kg/m2, average age of 65.5 years.||Exercise Intervention: All participants exercised for 50-60 min/d, 5 d/wk, for 12 weeks on either a treadmill (>75% of exercise time) or cycle ergometer. The intensity gradually increased from 60-65% max HR to 80-85% max HR. Diet Intervention: One group was asked not to alter their energy intake, while the second group reduced their energy intake by 500 kcal/d.||Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides||Significant reduction in total cholesterol, triglycerides, and LDL cholesterol in both the exercise only group and the exercise and caloric restriction group. No differences were found in HDL cholesterol for either group.||Small sample size.|
|Males (n=150), average age of 35.4 years.||Exercise Intervention: All subjected separated into sedentary (engaging in very little exercise), moderate exercise (playing football for 15 minutes), or vigorous exercise (15 minutes of vigorous and continuous jogging). Diet Intervention: Not controlled in this study||Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides||Significant reduction in total cholesterol, triglycerides, and LDL cholesterol (greater decrease in vigorous exercise).||Poor regulation of exercise, no regulation of diet prior to exercise|
|Males (n=15), sedentary, non-obese, young men (20-40 years).||Exercise Intervention: Exercise group (n=7) completed 2 months of supervised high-intensity interval training (3 session/wk; running at 60 and 90% of peak oxygen consumption in 4-min intervals for a total of 32 min; gross energy expenditure: ~446 kcal). Non-exercise control group Diet Intervention: Not controlled in this study||Free fatty acids, total plasma TG, VLDL-TG||Significant reduction VLDL-TG in exercise group alone. No other significant changes.||Small sample size, young, non-overweight subjects - difficult to correlate directly|
Exercise Effects on Epicardial Fat
Epicardial adipose tissue (EAT) shares an embryologic origin with visceral adipose tissue (VAT), suggesting that it is more pathologic than subcutaneous adipose tissue (SAT). Additionally, it is of particular interest due to its close proximity to the coronary arteries and myocardium. EAT thickness is strongly correlated with abdominal VAT, a primary factor in developing metabolic syndrome. Therefore, EAT may play a role in metabolic syndrome and cardiac disease by its increased intramyocardial triglyceride content or by displaying a similar adipokine profile as VAT. EAT can be subdivided into coronary peri-vascular adipose tissue (cEAT) and EAT over the myocardium (mEAT). A study by Company et al analyzed the effects of exercise on VAT, SAT, cEAT, and mEAT in pigs. The pigs were divided into sedentary and exercise groups, with the sedentary group confined to their pens and the exercise group performing moderate intensity (~70% of maximum HR) daily aerobic exercise on treadmills 5 days/week for a duration between 45 and 85 minutes. Following 16 weeks of training, the hearts of the pigs in each group were extracted and analyzed, primarily focused on 18 different mRNAs for their roles in inflammation, pro-oxidants, and adipocyte metabolism. The following results were found:
- Sedentary pigs showed almost no difference in gene expression between cEAT and mEAT.
- mRNAs involved with inflammation and oxidation including IL1-Ra, IL-6, IL-8, PAI-1, PDGS, eNOS, and cytochrome c oxidase were downregulated in response to aerobic exercise in mEAT but not cEAT. mEAT mass was also significantly higher in the exercise pigs. Therefore, aerobic exercise training reduced the inflammatory response in mEAT.
- VAT exhibited a different mRNA expression response to aerobic exercise than both mEAT and cEAT, downregulating genes involved with adipocyte metabolism such as FABP4, perilipin, adiponectin, and UCP-2.
- Only 2 (VEGFa and IL-6) of the 18 genes in SAT were altered by aerobic exercise training, compared to 6 for VAT and 10 for mEAT.
Therefore, the main result of the study is that epicardial adipose tissue can be subdivided into two metabolically different components that respond differently to exercise.
A second study analyzed the effect of aerobic exercise on epicardial adipose tissue in obese men. The men completed a 12-week exercise program (60-70% of maximal heart rate; 60 min/day, 3 days/wk) and underwent a transthoracic echocardiography to measure epicardial fat thickness. The following results were found:
- Significantly reduced epicardial fat thickness (p<0.001)
- A significant relationship between epicardial fat thickness and VAT.
- The change in VAT, the change in systolic BP, and the change in insulin sensitivity were independently related to the change in epicardial fat thickness.
Though the results of the two studies are slightly contradictory (in Company et al, the mEAT increased while in Kim et al the EAT decreased) following exercise, Company et al explain that these differences could be due to the human subjects being obese while the pigs were not.[39,36]
Exercise Effects on Hepatic Fat
Non-alcoholic fatty liver disease (NAFLD) is often a major component of the metabolic syndrome. Many studies suggest that increased daily physical activity is inversely related to NAFLD and that exercise training reduces fatty liver in obese patients with NAFLD.[40,41,42] Otsuka Long-Evans Tokushima Fatty (OLETF) rats are a commonly studied model of obesity and Type 2 diabetes and were used by Rector et al to analyze the effects of daily exercise on hepatic fatty acid oxidation. The rats were separated into those with (exercise) or without (sedentary) access to running wheels. Voluntary running was selected to approximate the more natural activity state of the animal. Food efficiency (total body weight gain divided by food intake) was calculated to assess energy expenditure, and daily running activity was recorded for the duration of the 16-week trial. The following results were found:
- Animal characteristics
- Significantly greater weight gain in sedentary versus exercise rats (by ~70%).
- Significantly reduced concentrations of serum glucose, insulin, triglycerides (TG), and free fatty acids (FFA) in the exercise rats.
- Significantly reduced fat pad masses (both omental and retroperiotoneal) in the exercise rats.
- Liver morphology
- Increased number of vacuoles in the sedentary rats.
- Significantly reduced percent positive staining and lipid droplet size in the exercise rats.
- Significantly reduced hepatic TG accumulation in exercise rats.
- Fatty acid oxidation
- Exercise significantly increased cytochrome c protein and palmitate oxidation concentrations.
- ACC and FAS
- Exercise training reduced acetyl-coenzyme A carboxylase (ACC) total content by ~35% and increased ACC Ser79 phosphorylation by ~35%.
- Exercise training also reduced fatty acid synthase (FAS) protein concentration by ~70%.
Therefore the main results of the study were that exercise suppressed weight gain and reduced the development of fatty liver. The reduced development of fatty liver appears to be associated with both increased hepatic fatty acid oxidation and reduced fatty acid synthesis. The complete oxidation of palmitate to CO2 was increased about three times in the exercise rats, but no difference was found in total liver fatty acid oxidation. This, combined with increases in cytochrome c protein, results in improved hepatic mitochondrial function (tighter coupling of β-oxidation, TCA cycle, and oxidative phosphorylation) that results in a more complete degradation of fatty acids in livers of obese rats. Fatty acid synthesis was decreased secondary to increased ACC phosphorylation and reduced total protein content of ACC which would increase fatty acid oxidation and decrease available substrate for FAS (which was also reduced by exercise).
Additionally, decreased hepatocyte exposure to lipids and hyperinsulemia occurred secondary to reduced serum TG and FFA, decreased body weight and fat pad mass, and improved insulin sensitivity. This helps to regulate lipogenesis and inhibits VLDL secretion.
A second study analyzed the effect of exercise on hepatic VLDL-triglyceride (VLDL-TG) secretion rate. Recent evidence has reported that hepatic VLDL-TG secretion rate is decreased following exercise, though the underlying mechanisms are poorly understood secondary to complexity. They hypothesized that microsomal triglyceride transfer protein (MTP) plays a central regulatory role in VLDL assembly as it may help to transfer lipids from the endoplasmic reticulum (ER) membrane to the apoB chain in the ER. Increased MTP leads to overproduction of VLDL-TG.
Following a 8-week exercise protocol consisting of running on a treadmill 5x/week for 15-60 min/day at 15-26 m/min on a 0-10% slope, the livers of rats fed either a standard diet (SD) or a high fat diet (HF) were analyzed. The authors found that hepatic MTP content was significantly lower in the training rats compared to the sedentary rats. This fact, combined with lower plasma VLDL-TG accumulation, explain that the liver of exercise-trained rats are able to decrease liver TG accumulation and reduce VLDL production regardless of diet.
In summary, moderate-high intensity aerobic exercise has many effects of fatty liver including increased fatty acid oxidation, decreased fatty acid synthesis, and reduction of MTP production, which decreases VLDL production.
Exercise Effects on the Pro-Thrombotic State
The pro-thrombotic state of patients with metabolic syndrome appears to be closely related to the levels of PAI-1 and fibrinogen circulating in the blood stream (as described on the cellular biology page). A study by Palomo et al  hypothesized that since TNF-α controls the levels of PAI-1 in endothelial cells and adipocytes, reducing the levels of TNF-α through exercise could reduce the levels of PAI-1. The exercise protocol used in the study on subjects with metabolic syndrome involved two groups: (1) non-intervened (NI-MS) and (2) intervened (I-MS) which required the subjects to complete three 60-minute sessions per week of controlled aerobic physical exercise for 18 weeks. The intensity began at 40% maximum HR and increased to 80% maximum HR in the later weeks of the study. The I-MS group also received nutritional education in the form of lectures and printed material. The following results were found:
- Significant reduction in TNF-α serum levels in the I-MS group.
- No significant changes in fibrinogen or plasma PAI-1 found in either group (I-MS and NI-MS).
- Changes in HDL-C and waist circumference were associated with changes in plasma PAI-1 levels.
The mechanistic explanation for this observation was not described in this study and could not be found. Folsom and colleagues found a reduction in plasma PAI-1 levels, but associated the change to weight loss versus exercising as their results were found regardless of amount of exercise .Torjesen and colleagues found no changes in plasma PAI-1 levels following a 1 year endurance training program. Somewhat supporting the results found by Torjesen et al, El-Sayed found a significant decrease in plasma PAI-1 levels after high intensity exercise, but not low-intensity exercise. The moderate-intensity exercise conducted in this study may not have been high enough to induce an effect on plasma PAI-1 levels, but this correlation needs further research.
A group of researchers have investigated the effects of moderate intensity exercise on mitochondria in sedentary adults with obesity and type II diabetes mellitus (DMII), compared to lean, sedentary adults. [49, 50, 51, 52] In a strategy conducive for comparison between groups, they utilized the same exercise intervention for several studies. The results of these studies on mitochondrial metabolic substrates and functions are synthesized and summarized in tables 3 and 4.
Common exercise intervention
The common intervention used in each study was a 16-20 week moderate intensity walking (treadmill or over ground) or cycling (stationary or over ground) based intervention. The first 4 weeks was 30 minutes at 60-70% maximal heart rate (HRmax), increased to 40 minutes in the second 4 weeks. The final progression was 40 minutes at 75% HRmax. At week 8, VO2max was determined to accurately prescribe the final progression. [49, 50, 51, 52]
Table 3. Effect of exercise on mitochondrial substrates
|Population||Cardiolipin (CL)||Mitochondrial DNA||NADH oxidase activity (by weight)||Citrate Synthase (CS)||β-HAD||NADH oxidase/ CS ratio||NADH oxidase/ β-HAD ratio||NADH oxidase/ CL|
|Lean, Exercise ||Increased||Increased||Increased||Increased||Increased||No change *Significantly higher than obese or DMII*||No change *Significantly higher than obese or DMII*||No change|
|DMII, Obese, Exercise [50, 52]||Increased (55%)||Modest increase (20%)/ Disproportionate to CL||Increased||Increased||Increased||No change*||No change*||Not reported|
|Obese, Diet, Exercise [49, 51, 52]||Increased||No change||Increased||Increased (less than NADH increase)||Increased||No change*||No change*||No change|
|Obese, Diet, Sedentary [49, 51]||No change||No change||No change||No change||Not reported||No change*||Not reported||No change|
Table 3 Key
- Cardiolipin (CL) - Phospholipid in the mitochondrial inner membrane, marker of mitochondrial biogenesis by increased inner membrane surface area where the electron transport chain resides 
- Mitochondrial DNA - Genetic information for mitochondrial proteins 
- NADH Oxidase - Indicates electron transport chain activity from complex I to complex IV 
- Citrate synthase (CS) - Key enzyme of TCA cycle and reflects mitochondrial density in skeletal muscle 
- β-HAD (β-hydroxyacyl-CoA dehydrogenase) - Key enzyme of β-oxidation pathway 
Table 4. Effect of exercise on whole body measures and mitochondrial function
|Population||Weight||VO2max||Insulin sensitivity||Mitochondrial biogenesis||ETC activity||Mitochondrial size||Mitochondrial density|
|Lean, Exercise||No change||No change||No change||Increased||Increased||Not analyzed||Not analyzed|
|DMII, Obese, Exercise [50, 52]||Weight loss||Increased||Improved||Increased||Increased||Increased||Increased (67%)|
|Obese, Diet, Exercise [49, 51, 52]||About 10% weight loss||Increased||Improved||Increased||Increased||No change||Increased|
|Obese, Diet, Sedentary [49, 51]||About 10% weight loss||No change||Improved||No change||No change||Decreased||No change|
Table 4 Key and Conclusions
- Insulin sensitivity – Measured by euglycemic clamps
- Improvements in skeletal muscle insulin sensitivity occurred weight loss and diet restriction, regardless of exercise. This demonstrates that insulin sensitivity improvement occurs independently of improvements in mitochondrial capacity. 
- Mitochondrial biogenesis – As indicated by changes in cardiolipin, NADH oxidase, citrate synthase, β-HAD levels.
- Electron transport chain (ETC) activity – As indicated by NADH oxidase and roteone-sensitive NADH:O2 oxidoreductase activity
- At baseline, obese and DMII subjects demonstrated significantly reduced ETC activity compared to lean controls. This is also demonstrated when ETC activity is normalized to cardiolipin levels. However this deficiency is not evident in citrate synthase or B-HAD activity, indicating an imbalance between ETC activity and TCA/β-oxidation. Although all levels improved in response to exercise, the imbalance remained. [52, 50, 49]
- Mitochondrial size – Measured by transelectron microscopy 
- Weight loss secondary to caloric restriction resulted in decreased mitochondrial size in obese adults, whereas exercise increased mitochondrial size in obese adults with DMII. The lack of significant change in mitochondrial size in obese adults with weight loss due to exercise and caloric restriction may be due of the offsetting effects of the two interventions. 
- Mitochondrial density – Measured by transelectron microscopy 
- Increases in mitochondrial density and cardiolipin significantly correlated to increases in citrate synthase and NADH oxidase activity. Mitochondrial density increases also significantly correlated with increased insulin sensitivity in patients with DMII, however a causal relationship cannot be determined from these results. 
Moderate intensity (60-75% maximal heart rate) aerobic exercise for 30-40 minutes 4-6 days per week has demonstrated improvements in oxidative capacity mitochondrial function in obese and type II diabetic adults compared to weight loss (caloric restriction) alone. [49, 50, 51, 52]
Moderate and high intensity aerobic exercise increase the expression of PGC-1α, a master regulator of mitochondrial biogenesis. [53, 54] Increased PGC-1α expression may enhance fatty acid oxidation in skeletal muscle.
- A significant and comparable increase in PGC-1α expression in skeletal muscle mitochondria was found after 10 consecutive days of moderate intensity exercise in lean, obese, and previously obese (>1 year post gastric bypass with >50lb weight loss) adults. Subjects exercised 60 minutes/day at 70% VO2peak on a cycle ergometer. 
- A study by Haram et al.  compared the effects of aerobic interval training and continuous moderate exercise on PGC-1α expression in a rat model of metabolic syndrome. Both programs consisted of running at a 25° incline, 5 days/week. Aerobic interval training was completed 1 hour/day and consisted of 4 minute periods of running at 85-90% VO2max, followed by a 3 minute recovery at 70% VO2max. Continuous moderate exercise was completed for 1.5-2 hours/day and consisted of continuous running at 70% VO2max. Distances covered were comparable, thus accounting for the time discrepancies. Both groups had significant increases in PGC-1α expression, however AIT elicited significantly greater increase with AIT and CME resulting in 12 fold and 6 fold increase in PGC-1α expression over sedentary controls respectively. 
A 10-week cycling intervention demonstrated no significant effect on mitochondrial reactive oxygen species (ROS) release in obese men with and without type II diabetes.  However subjects with type II DM tended to have increased baseline levels of ROS, which demonstratd a decreasing trend after training. As a whole group, a significant increase (72%) of UCP3 (uncoupling protein 3) was found, as well as a 50% increase in citrate synthase (CS). The increased UCP3/CS ratio may explain the relatively unchanged levels of ROS. The exercise intervention specifically consisted of 20-35 minutes of cycling at ~65% VO2max (as monitored by HR) 4-5 times per week.
Metabolic syndrome creates a persistent adaptation to perceived stress in the body, thus creating increased activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. Often, when a system is exposed to a consistent stressor, the HPA axis diminishes its activation, called stress habituation; this phenomenon is decreased in metabolic syndrome. This hyperactivity of the HPA axis leads to increased levels of cortisol in the body; cortisol increases gluconeogenesis, thus creating higher glucose levels in the blood which can contribute to decreased insulin sensitivity.  Cortisol is also known to be a catabolic hormone, leading to decreased muscle mass. 
In healthy individuals, cortisol levels have been shown to increase for several hours after moderate aerobic exercise (55% of VO2 max) in response to this acute stress.  This phenomenon has a duration dose response, meaning that cortisol levels will increase as the duration of exercise increases. The researchers found that increases in cortisol were significantly greater in exercise of greater than 40 minutes in duration, therefore, it may be detrimental to partake in exercise bouts longer than 40 minutes at this given intensity. The researchers state that elevated cortisol shifts amino acid use from protein synthesis to gluconeogenesis.One studyexamined the effect of differing intensities on cortisol levels in moderately trained men. Men performed one bout of 30 minutes of cycling ergometry at intensities of 40, 60 and 80% of their individual VO2 max; cortisol levels were taken immediately before and after the session as well as at rest on a separate day. The results showed that intensities of 60 and 80% caused an increased amount of cortisol while intensities at 40% caused a net decrease in cortisol. More highly trained individuals typically have a higher intensity threshold necessary to provoke an increase in cortisol,  therefore an increase in cortisol would presumably occur at lower exercise intensities in subjects with metabolic syndrome. It is important to remember that these mentioned effects on cortisol are in the short-term, and it is unclear at this point how these short term effects on cortisol may affect long-term hypercortisolism in metabolic syndrome.
While an increase in short-term cortisol levels is normal in healthy individuals, a decrease in cortisol has been shown in healthy mice partaking in aerobic exercise over a sustained period of time. Mice partaking in an intervention of wheel walking of 4 km per day for 4 weeks had a decrease in cortisol when compared to their levels prior to the intervention.  It is important to realize, however, that too much exercise may be detrimental to the positive effects on the HPA axis. Chronic, excessive exercise, such as marathon running, leads to increased activity of the HPA axisthough it is not known to what extent in patients with metabolic syndrome when compared to the general population.
In regard to resistance training, several studies have looked at the long term adaptation response in cortisol, and found that resistance training does not have an effect on long-term cortisol concentrations.
While few studies examine the differences of exercise’s effects on cortisol comparing healthy and obese individuals, one study sheds light on how obesity and altered cortisol function could lead to differences in response to exercise. The study examined obese men, though not necessarily having all criteria of metabolic syndrome. After performing a cycle ergometer bout of 30 minutes at 60% of V02 max, the obese subjects had increased cortisol levels when compared to lean, healthy controls. The researchers state that these abnormally increased cortisol levels would therefore increase gluconeogenesis that would cause a reduced potential for fat oxidation.
Exercise dosage - a unique perspective
The effects of differing exercise dosage on cellular effects was examined in a unique rat model of metabolic syndrome.  In an effort to model the multifactorial genetic profile of metabolic syndrome, a rat model was developed by artificially breeding rats that have low intrinsic aerobic treadmill running capacity over 15 generations. The result was a rat phenotype that symptomatically resembles the many components of metabolic syndrome including obesity, insulin resistance, dyslipidemia, and hypertension. The study compared the effects of two different moderate-high intensity aerobic programs: aerobic interval training versus continuous moderate exercise. Both programs consisted of running at a 25° incline, 5 days/week, and a warm up time of 10 minute at 50-60% VO2max. Aerobic interval training (AIT) was completed 1 hour/day and consisted of 4 minute periods of running at 85-90% VO2max, followed by a 3 minute recovery at 70% VO2max. Continuous moderate exercise (CME) was completed for 1.5-2 hours/day and consisted of continuous running at 70% VO2max. Distances covered were comparable, thus accounting for the time discrepancies. VO2max was measured at the start of every week to maintain accurate intensities for training. The training was performed until VO2max plateaued for 3 consecutive weeks, resulting in about an 8 week training period.
Both groups demonstrated significant increases in VO2max, weight loss, and retroperitoneal fat loss compared to sedentary controls, however there was no significant difference between groups. AIT demonstrated significantly greater improvements in systolic blood pressure, PGC-1α expression, serca 1 and serca 2 levels (responsible for calcium removal in skeletal muscle associated with contraction), and endothelial function compared to CME and sedentary controls; CME also demonstrated improvements in all these levels except serca 1 and 2 compared to sedentary controls, however to a lesser degree.
Summary of Exercise Guidelines
Based on the evidence reported above, the following exercise recommendations can be made:
Intensity, Frequency and Duration
Moderate and/or vigorous intensity exercise (65%-85% heart rate max) is recommended for adults with metabolic syndrome. For safety when initiating an exercise program, up to a 2 month ramp up period should be used prior to participating in moderate intensity activity. After this intensity is reached, research supports the continual increase in intensity up to 85%-90% of heart rate max. Longer duration exercise (≥180 minutes/week total;3-5 days/week of exercise) is recommended in order to achieve optimal improvement in:
- central adipose tissue distribution
- insulin sensitivity
- glucose tolerance
- cytokine function and response
- inflammation response
- lipid profile
- mitochondrial capacity
- HPA axis acitivty
- Aerobic exercise (i.e. use of treadmills, ellipticals or cycle ergometers) has been shown to improve overall cellular function in people with metabolic syndrome.
- Resistive exercise (weight training of large muscle groups) in combination with aerobic exercise has been shown to specifically improve insulin sensitivity in people with metabolic syndrome.
Diet and Nutrition
Diet and exercise improves ability to oxidize lipids, which is associated with a normalization of adiponectin, leptin, and resistin levels resulting in improved insulin sensitivity. A 500 kcal per day cut in calories from normal resulted in a 39.1% increase in adiponectin and when combined with moderate exercise resulted in a 79.7% increase in adiponectin. In Christiansen et al.'s study, diet only and diet plus exercise increased circulating adiponectin by approximately 20% more than exercise only. Anthroprometric changes were also greater in the diet only and diet plus exercise groups when compared with exercise only. After 6 months of a low intensity exercise program combined with a 500 kcal deficit vs. daily expenditure, 10 of the 14 females who started the study with metabolic syndrome no longer met the IDF criteria for metabolic syndrome. In a mouse study, calorie restriction and endurance exercise improved body composition along with reduced resistin, leptin, and RBP-4.
A study by Camhi et al. evaluated the effects of diet intervention, exercise intervention or diet + exercise intervention in a group of adults diagnosed with metabolic syndrome. The diet intervention consisted of 1) reduced total fat to <30% of total caloric intake, 2)reduced saturated fat to <7% of total caloric intake, and 3) reduced dietary cholesterol to <200 mg/day. They found that diet intervention alone and diet + exercise intervention significantly improved circulating CRP levels in both men and women greater than the effect seen in the exercise alone intervention indicating that diet intervention is a necessary component in the treatment of a person with metabolic syndrome.
Along with caloric restriction, the components of a person's diet influence metabolic pathways. Diets that have a high monosaturated to saturated fat ratio, such as the Mediterranean diet, have less incidence of metabolic syndrome.
In regards to the relationship between diet and improvements of insulin sensitivity no relationship was found to support the need for dieting. Three studies looked at the improvements of insulin sensitivity between exercise for weight loss or calorie restriction for weight loss. One study found that there was not a significant different between the two methods,  while the other two studies found that there were better improvements in insulin sensitivity with exercise alone. [11,13]. The literature does not currently support the use of diet to specifically alter insulin sensitivity at the cellular level in patients with metabolic syndrome.
Areas for Future Research
Further research is needed to examine the effect of resistive exercise training on the various cellular pathways that are dysregulated in people with metabolic syndrome (i.e. fat distribution, mitochondrial capacity, HPA axis, inflammation, cytokine activity, dyslipidemia). Currently, research only supports the use of resistive exercise training in combination with aerobic exercise to improve insulin sensitivity in adults with metabolic syndrome. Also, more research needs to be done to evaluate possible detrimental effects of exercise on the cellular biology in a person with metabolic syndrome (i.e. effect of reactive oxygen species and oxidative stress after acute and chronic exercise, effect of too vigorous of exercise on the HPA axis activity or other aspects of cellular regulation).