Introduction

Metabolic syndrome is a cluster of interrelated risk factors (visceral obesity, dyslipidemia, hyperglycemia, and hypertension) (1) that increase susceptibility to cardiovascular disease (2, 3) and type 2 diabetes (4, 5). The National Cholesterol Education Program's Adult Treatment Panel III report (6) stated that the increasing prevalence of obesity has been accompanied by a parallel increase in the prevalence of metabolic syndrome, which together constitutes the "obesity epidemic."

Cross-sectional data indicate that high levels of cardiorespiratory fitness are associated with low prevalence of metabolic syndrome (7, 8, 9). Several prospective studies have found that cardiorespiratory fitness is a significant predictor for metabolic syndrome incidence (10, 11). Another study found that 20 weeks of aerobic exercise training reduced metabolic syndrome prevalence (12). Clinical intervention studies in obese people have also revealed that regular aerobic exercise training clearly improves risk factors for metabolic syndrome (13, 14).

Detecting metabolic syndrome in asymptomatic obese individuals is useful in identifying high-risk individuals for intensive primary preventive therapy (15), and lifestyle therapy is recognized as an important approach in the various clinical and educational settings of obesity treatment. However, little is known of the effects of diet and/or aerobic exercise training on metabolic syndrome improvement in obese individuals.

We have investigated these issues in overweight and obese Japanese women. On the basis of the studies cited above, we hypothesized that change in cardiorespiratory fitness, defined as maximal oxygen uptake (O_2max)¹, would be a predictor for improvement in metabolic syndrome in obese subjects during weight reduction. We first determined whether cardiorespiratory fitness was associated with metabolic syndrome prevalence at baseline. Next, we assigned subjects with metabolic syndrome to two treatment groups, which received diet therapy alone or with aerobic exercise training, and we investigated the effects of cardiorespiratory fitness change and these two treatments on metabolic syndrome improvement during weight reduction.

Research Methods and Procedures

Subjects

Participants were sedentary overweight and obese Japanese women who were recruited through advertisements in local newspapers in Ibaraki prefecture, Japan, and participated in a 14-week weight-reduction program between 2000 and 2004. Before the program, we excluded subjects who smoked, had concomitant renal, hepatic, or cardiac disease, or were being treated with hormone replacement or drugs, which could affect the variables of the study. Consequently, 459 women, 34 to 66 years of age, were chosen as subjects (Table 1) after they met the following criteria: 1) sedentariness, defined as exercise-induced energy expenditure of <60 minutes/wk, and 2) overweight or obesity, defined as a BMI of, respectively, >25 kg/m² and >30 kg/m² (16). Of these women, 185 were postmenopausal and 274 were premenopausal. Menopause was defined as the absence of menses for at least 12 months, as reported by questionnaire. This study conformed to the principles outlined in the Helsinki Declaration and was approved by the Review Board of the University of Tsukuba. The aim and design of the study were explained to each subject before she gave her written, informed consent.

Table 1 - Baseline characteristics of subjects (n = 459).

Full table

Research Procedures

First, we cross-sectionally examined the relationship between cardiorespiratory fitness and metabolic syndrome prevalence in all subjects. Next, 67 subjects were diagnosed as having the metabolic syndrome according to the criteria for the Japanese population, which are described below (17). To increase subjects' adherence to the weight loss programs, the subjects' personal lifestyles (occupations, daily schedules, etc.) and preferences were taken into account, and the 67 subjects were assigned to two 14-week weight-reduction programs consisting of a low-calorie diet (n = 24; target energy intake, 1200 kcal/d) or the diet-plus-aerobic exercise (n = 43). Three subjects in the diet alone group and 5 in the diet plus exercise group were unable to complete the study successfully for personal reasons. As a consequence, 21 subjects in the diet alone group and 38 subjects in the diet plus exercise group completed the study requirements. Assays and measurements were carried out before and after the 14-week intervention period. We prospectively examined the relationship between cardiorespiratory fitness change and metabolic syndrome improvement in response to weight reduction.

Anthropometric Variables

Body mass was measured to the nearest 0.1 kg using a digital scale, height was measured to the nearest 0.1 cm using a wall-mounted stadiometer, and BMI was calculated as mass (kg) divided by height squared (m²). Waist girth was measured to the nearest 0.1 cm at the level of the umbilicus with subjects in the standing position.

Visceral Fat Area by CT Scans

Visceral fat area (cm²) was measured at the level of the umbilicus (L4–L5) using computed tomography (CT) scans (SCT-6800TX, Shimadzu, Tokyo, Japan) performed on subjects in the supine position and was calculated using a computer software program (FatScan, N2system, Osaka, Japan) (18). The intra-class correlation for repeated determinations of visceral fat area in our laboratory was 0.99.

Definition of Metabolic Syndrome

For the Japanese population, the Examination Committee of Criteria for "Metabolic Syndrome" in Japan (17) defined metabolic syndrome as the presence of visceral fat obesity (visceral fat area 100 cm²) and two or more of the following criteria: 1) triglycerides 1.70 mM (150 mg/dL) and/or high-density lipoprotein cholesterol <1.04 mM (40 mg/dL), 2) systolic blood pressure 140 mm Hg and/or diastolic blood pressure 90 mm Hg, and 3) fasting plasma glucose 6.1 mM (110 mg/dL). Systolic and diastolic blood pressures were taken from the left arm using a sphygmomanometer after the subjects rested at least 20 minutes in a sitting position. Cuff sizes were selected based on upper arm girth and length. A blood sample of 10 mL was drawn from each subject after an overnight fast. Triglycerides were determined enzymatically, and fasting plasma glucose was assayed by a glucose oxidase method. Serum high-density lipoprotein-cholesterol was measured by the heparin-manganese precipitation method.

Maximal Oxygen Uptake

Maximal oxygen uptake (O_2max, mL/kg per min and mL/min) was determined during a graded exercise test using a cycle ergometer (818E, Monark, Stockholm, Sweden). After a 2-minute warm-up, the subject started with a workload of 15 W, which was increased by 15 W each minute until volitional exhaustion occurred. Pulmonary ventilation and gas exchange were measured breath-by-breath with an online data acquisition system (Oxycon System, Mijnhardt, Breda, Netherlands).

Diet and Exercise Regimens

Dietary Protocol.

Subjects were instructed to take a well-balanced supplemental food product (MicroDiet, SunnyHealth, Nagano, Japan) every day. It was developed for very low-energy diets (170 kcal per pack) and is comprised of protein, carbohydrates, fat, various amino acids, vitamins, and minerals. Two other meals per day were allowed, consisting, on average, of 240 kcal of protein, 480 kcal of carbohydrate, and 240 kcal of fat. Subjects also kept daily food diaries during the 14-week intervention period and learned about proper daily nutrition through weekly lectures and counseling by skilled dieticians.

Exercise Protocol.

In addition to restricting energy intake, the subjects from the diet plus exercise training group performed a bench-stepping exercise 3 days/wk for 45 minutes per session, supervised in the hospital by two or three physical trainers. The bench-stepping exercise is a combination exercise of low impact aerobic dance and stepping with a step bench (10 to 20 cm high) (19). The exercise started with basic steps for the first 4 weeks and then progressed to combination of basic steps and lunge steps for the next 6 weeks, and finally progressed to more advanced lunge steps for the last 4 weeks. Subjects were instructed to perform the aerobic dance at a level that raised their heart rate to 70% to 85% of the corresponding heart rate at their O_2max. The target Borg's scale (ratings of perceived exertion) (20) ranged from 13 (fairly hard) to 17 (very hard).

Statistical Analysis

Values are mean standard deviation. Paired t tests were used to assess differences between variables before and after the weight-reduction intervention period. Unpaired t tests were used to test difference in variables between the two treatment groups. Qualitative data were analyzed by a ² test. We used logistic regression to estimate odds ratios and 95% confidence intervals (CIs) as an index of the strength of associations between cardiorespiratory fitness and metabolic syndrome prevalence or improvement, and between treatment (diet alone vs. diet plus exercise) and metabolic syndrome improvement. Multivariate analyses were adjusted for age (years), menopause (yes/no), BMI (kg/m²), and body weight change (kg). General linear model analyses [ repeated-measure two-by-two way (baseline vs. after treatment) ANOVA with post hoc tests] were used to test for difference in measurement variables between groups with diet alone and diet plus exercise, and between baseline and after treatment. In each statistical analysis, probability values below 0.05 were regarded as significant. The data were analyzed with the Statistical Analysis System, version 9.01 for Microsoft Windows (SAS Institute, Inc., Cary, NC).

Results

At baseline, we observed an inverse gradient (linear trend, p < 0.05) of age- and BMI-adjusted odds ratios for metabolic syndrome prevalence in the low (average O_2max, 20.8 mL/kg per min), middle (average O_2max, 25.2 mL/kg per min), and upper (average O_2max, 29.5 mL/kg per min) thirds of O_2max. They were 1.0 (referent), 0.50 (95% CI, 0.26 to 0.95), and 0.39 (95% CI, 0.14 to 0.96), respectively (linear trend, p = 0.02) (Table 2). The significant trend (linear trend, p = 0.03) remained after adjustment for age, BMI, and menopausal status. The adjusted risks of metabolic syndrome were 48% (- 6% to 75% ) and 63% (- 4% to 87% ) lower in the middle and upper thirds of fitness, respectively, compared with the lower third. On average, each 1 mL/kg per min increment in O_2max was associated with 7% lower risk of metabolic syndrome.

Table 2 - Odds ratios and 95% CIs for metabolic syndrome according to O_2max (mL/kg per min).

Full table

Sixty-seven women (15% of all subjects) were diagnosed as having metabolic syndrome. The subjects were assigned to two groups, treated with a low-calorie diet (n = 24) or the diet-plus-aerobic exercise training (n = 43) (Table 3). Three subjects in the diet alone group and five in the diet plus exercise group were unable to complete the weight-reduction program successfully, for personal reasons. Consequently, 21 subjects in the diet alone group and 38 subjects in the diet plus exercise group were included in the final analysis. The average weight reductions in the diet group and diet plus exercise group were 6.0 kg and 8.8 kg, respectively. The prevalence of metabolic syndrome and metabolic syndrome risk factors was significantly decreased and improved in both groups. For the group treated with diet alone, of the 21 subjects with the metabolic syndrome at baseline, 15 (71% ) were no longer diagnosed with the metabolic syndrome after the weight-loss treatment. For the group treated with diet plus exercise, of the 38 subjects with the metabolic syndrome at baseline, 36 (95% ) were no longer diagnosed as having the metabolic syndrome after the weight-loss treatment.

Table 3 - Descriptive characteristics of subjects with metabolic syndrome at baseline (n = 67) and after treatment (n = 59).

Full table

We next examined whether treatment (diet alone vs. diet plus exercise) affected metabolic syndrome improvement in response to weight reduction (Table 4). The adjusted odds ratios in the groups with diet alone and diet plus exercise for metabolic syndrome improvement were 1.0 (referent) and 3.68 (95% CI, 1.02 to 17.6; linear trend, p = 0.04).

Table 4 - Odds ratios and 95% confidence intervals for improvement of metabolic syndrome according to treatment.

Full table

Discussion

Several organizations have recommended clinical criteria for the diagnosis of the metabolic syndrome (1, 21). There are some slight differences in the criteria for diagnosis of the metabolic syndrome used by these organizations. According to the definition of the World Health Organization (22), insulin resistance is a required component and two other risk factors are sufficient for a diagnosis of metabolic syndrome. The National Cholesterol Education Program's Adult Treatment Panel III has stated that when three of five listed characteristics are present, a diagnosis of metabolic syndrome can be made (6). The criteria of the International Diabetes Federation include "central obesity" as an essential component and ethnic-specific values for waist girth (23). In the present study, we used Japanese-specific criteria recommended by the Examination Committee of Criteria for Metabolic Syndrome in Japan (17). This is in accordance with the International Diabetes Federation definition, whereas a slight difference was found in the criteria of low high-density lipoprotein cholesterol and high fasting plasma glucose between the two organizations. It is well known that Japanese individuals are likely to develop obesity-related disorders with even mild obesity (24). Inter-relations among anthropometric variables, body composition, fat distribution, and lipid/glucose metabolism, which may be affected by genetic factors, are quite different in the Japanese, U.S., and European populations. Therefore, we decided to use the Japanese-specific definition of metabolic syndrome.

A few prospective studies have revealed that physical activity and cardiorespiratory fitness are predictors of metabolic syndrome incidence (10, 11). One study reported that a 20-week supervised aerobic exercise training reduced metabolic syndrome prevalence by 31% (12). The subjects in the above studies, however, were not all obese. Clinical intervention studies have shown that regular aerobic exercise training clearly improved risk factors for metabolic syndrome in obese people (13, 14), but no study, to our knowledge, has confirmed the improvement of metabolic syndrome with increased cardiorespiratory fitness. To our knowledge, the present study is, therefore, the first to investigate the association between cardiorespiratory fitness and metabolic syndrome in overweight and obese populations.

Table 2 suggests that, even with overweight and obesity, high O_2max is associated with low prevalence of metabolic syndrome. This finding is in accordance with previous cross-sectional studies on the association of physical activity and cardiorespiratory fitness with the prevalence of metabolic syndrome (7, 8, 9). In obese patients, high cardiorespiratory fitness may prevent metabolic syndrome. Hence, clinicians should counsel their sedentary patients with obesity to become more physically active.

It is well known that an excess visceral fat accumulation is strongly associated with a high prevalence of risk factors for coronary heart disease, such as lipid metabolic disorders, hypertension, and type 2 diabetes. Moreover, several studies have shown that the visceral fat area above which metabolic disturbances increase is 100 or 110 cm² (25, 26). Japan Society for the Study of Obesity has adopted visceral fat area of 100 cm² as the cut-off point for diagnosing high-risk obesity (16). Our data showed that average visceral fat area became <100 cm² in the group treated with diet plus exercise after weight loss, but that still remained >100 cm² in the group with diet alone. Table 3 shows that, although the prevalence of metabolic syndrome and metabolic syndrome risk factors was significantly decreased in both groups, the decreases tended to be larger in the group with diet plus exercise compared with the diet alone group. These data were accordance with previous studies on the association of visceral fat accumulation with the prevalence of risk factors for coronary heart disease.

In the present study, relative values of O_2max (unit, mL/kg per min) increased significantly between baseline and after weight reduction, whereas a significant increase was not found in absolute values of O_2max (unit, mL/min), even in the group treated with diet plus exercise. A study design that includes exercise of higher intensity and greater frequency and a longer intervention period, which could increase cardiorespiratory fitness, might be needed.

Aerobic exercise training may, however, be essential in treating obese patients with metabolic syndrome, even if the exercise does not increase their O_2max. The adjusted odds ratio for metabolic syndrome improvement in our study was 3.68 in the group with diet plus exercise training compared with diet alone, when adjusted for age and body weight change. That is to say, adding aerobic exercise training to dietary weight reduction may have a synergistic effect on the improvement of risk factors for metabolic syndrome. This is partly supported by our previous studies (27, 28). In one (27), we found that the addition of exercise training contributes to the maintenance of fat-free mass and might be more effective for improving physical fitness and risk factors for coronary heart disease during weight reduction in obese women, compared with diet alone. Another study revealed that a 14-week weight-loss program with diet plus aerobic exercise training reduced visceral adipose tissue by a factor of 1.3 (diet plus exercise, 49.3 cm²; diet alone, 37.8 cm² by CT scans) compared with diet alone, after adjustment for age, menopausal status, and body weight reduction (28). These studies suggest that adding aerobic exercise training to a dietary weight-reduction program further reduces visceral adipose tissue and further improves coronary heart disease risk factors compared with diet alone, even if weight reduction is the same with either treatment.

This study has some limitations. Our findings apply primarily to overweight and obese Japanese women. Although the external validity of our data is limited, the homogeneity of our subjects reduces confounding by sociodemographic factors, thus enhancing its internal validity. Second, subjects were not randomized to the treatments. Because our goal, in particular, was to increase subjects' adherence to the weight loss programs, the subjects' personal lifestyles and preferences were preferentially taken into account. Consequently, the numbers of subjects were imbalanced in two treatment groups. The study design without randomization may be concomitant with a type II error because of some confounding variables. This factor might partly preclude our definitive conclusion. However, at baseline, no differences were found in any variables between the groups treated with diet alone and with diet plus exercise. This suggests that assigning rather than randomizing subjects had little, if any, influence on the measurement variables.

In summary, our cross-sectional data suggest that, for overweight and obese women, a physically active lifestyle and maintenance of high cardiorespiratory fitness can be useful in primary prevention of metabolic syndrome. Our interventional study revealed that, for overweight and obese women with metabolic syndrome, adding aerobic exercise training to dietary weight reduction is a more effective (adjusted odds ratio = 3.68) treatment for improving metabolic syndrome than diet alone. However, weight-loss intervention trials of longer duration, with more frequent, higher-intensity exercise training and larger samples of obese patients with metabolic syndrome are needed to confirm the association between cardiorespiratory fitness change and metabolic syndrome improvement.

Notes

¹ Nonstandard abbreviations: O_2max, maximal oxygen uptake; CT, computed tomography; CI, confidence interval.

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Acknowledgments

This work was supported in part by Grants-in-Aid from the Japanese Society of Physical Fitness and Sports Medicine (1998–2000), by Grants-in-Aid from the Uehara Memorial Foundation (2005), by the Tanaka Project (2004–2006) of TARA (Tsukuba Advanced Research Alliance) at University of Tsukuba, and by the twenty-first century COE (Center of Excellence) program, Ministry of Education, Culture, Sports, Science and Technology (2002–2006 Nishihira Project: Promotion of Health and Sport Scientific Research).