ARIKAWA, ANDREA Y.1; THOMAS, WILLIAM2; SCHMITZ, KATHRYN H.3; KURZER, MINDY S.1
Regular exercise has been shown to protect against many chronic diseases, including atherosclerosis, type 2 diabetes, and colon and breast cancer (4,14). One mechanism by which exercise may protect against chronic diseases is via a reduction in systemic inflammation. Chronic low-grade inflammation has been described as a condition marked by a two- to threefold increase in levels of inflammatory markers such as C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β (41). Some of these markers have been correlated with low aerobic fitness and a sedentary lifestyle (15,28,39). Furthermore, CRP has been associated with a higher incidence of breast cancer and a significant increase in overall cancer incidence (21).
Adiponectin and leptin are proteins secreted by adipose tissue (adipokines) that are also implicated in the inflammatory process. Leptin upregulates phagocytosis and cytokine production and induces oxidative stress in endothelial cells, thus acting as a proinflammatory factor (13). Adiponectin reduces the production of TNF-α (32) and induces the production of anti-inflammatory cytokines (47). A systematic review examining the effects of exercise on adiponectin levels reported that exercise increased adiponectin levels in 38% of the eight randomized controlled trials identified (42). Although these trials were conducted in a wide range of populations, none included young healthy women, and the authors concluded that more evidence was needed for younger age groups. This is of great importance to public health because if exercise can favorably change levels of inflammatory markers in younger populations, it may protect against the development of chronic diseases later in life.
There are few large controlled trials examining the effects of aerobic exercise training on markers of inflammation and adipokines in younger populations. Previous studies in younger populations have had smaller sample sizes (11,12) and have been published before 2008, when the most recent physical activity guidelines for Americans were released. This publication recommends that adults do at least 150 min·wk−1 of moderate-intensity or 75 min·wk−1 of vigorous-intensity physical activity for substantial health benefits, plus muscle strengthening activities involving all major muscle groups two or more days a week for additional health benefits (45). This study investigated the effects of an aerobic exercise program consistent with current guidelines for physical activity on adipokines and inflammatory markers in healthy young women. We hypothesized that aerobic exercise training would reduce the levels of proinflammatory markers (CRP, SAA, and leptin) and increase the levels of the anti-inflammatory marker adiponectin.
This study was an exercise intervention trial examining the effects of a 16-wk exercise intervention on biomarkers associated with breast cancer risk (the WISER trial), which is described in detail elsewhere (2). A total of 391 participants were randomized into the WISER trial. Briefly, recruitment methods included e-mails to students and employees of universities and of the county, as well as letters sent to childcare workers, posted fliers, and print advertisements. Figure 1 shows the flow diagram of the WISER trial. Inclusion criteria were as follows: age 18-30 yr; body mass index (BMI) between 18.5 and 40 kg·m−2; sedentary, defined as not currently participating in any habitual exercise training of moderate to vigorous intensity for two or fewer sessions weekly; self-reported menstrual cycle length of 24-35 d during the 2 months before entering the study; nonsmoker; intact ovaries and uterus; no history of gynecologic problems such as fibroids, endometriosis, or polycystic ovary syndrome; no hormonal contraception use (for the past 3 months for oral, patch, and vaginal ring methods and past 12 months for IUDs with hormones and depo-provera); no medical conditions or medications that would prohibit participation in a vigorous program of weight bearing exercise or would negatively affect our ability to test our hypotheses; controlled hypertension; no history of cancer within the past 5 yr, excluding nonmelanoma skin cancers; not currently or recently (past 6 months) pregnant; not planning to become pregnant during the study period; alcohol consumption equal to or less than seven servings per week; not planning to move away from the Twin Cities area during the period of the study; stable weight (no changes > 10% for past year); and not currently trying to lose weight (by dieting, exercise, or other means). The WISER trial was approved by the University of Minnesota Human Subjects Review Committee. Written informed consent was obtained from all participants at the orientation sessions before beginning any study activities. Randomization was stratified by baseline BMI and age to achieve a ratio of 60:40 (treatment-control) in each stratum.
FIGURE 1-Diagram of ...Image Tools
Participants randomized into the exercise group were asked to attend five exercise sessions per week. Each session was approximately 45 min in length: 30 min of weight bearing aerobic exercise at a specified intensity based on age-predicted HRmax and 5 min each for the warm-up, cool-down, and stretching. Exercise intensity was set at 65%-70% of age-predicted HRmax for the first 4 wk of exercise (HRmax = 220 − age), 70%-75% of HRmax for weeks 5-8, 75%-80% of HRmax for weeks 9-12, and 80%-85% of HRmax for the final stage, which lasted until they completed the study (day 5 of the sixth menstrual cycle). The final stage ranged from 2 to 6 wk, depending on the participants' menstrual cycle length. Participants wore an HR monitor (Polar Electro, Inc., Lake Success, NY), completed workout logs, and worked with a certified personal trainer for ongoing support and monitoring of their adherence to the protocol. At the first several exercise sessions, the trainer instructed participants in the proper use of the HR monitors, as well as warm-up, cool-down, stretches, and aerobic exercise equipment safety and once a week thereafter to provide ongoing support and monitoring. Furthermore, instruction was provided regarding completing the exercise logs, which involved recording exercise date, time of day and duration, average HR from the Polar HR monitor, equipment used for each exercise session, and any additional comments. At the weekly meetings with the participants, the trainers reviewed exercise logs and the specifics of the exercise protocol to ensure safety as well as answer any questions or concerns from participants. Those randomized into the control group were asked to maintain their usual levels of physical activity and to not engage in any new exercise program during study participation. All participants were asked to maintain their usual diets.
Blood samples were collected in the morning after a 10-h fast, during the midfollicular phase of participants' menstrual cycles (between days 7 and 10 of the cycle) at baseline and at the end of the intervention period, which ranged from 14 to 18 wk, based on the participants' menstrual cycle length. Participants were instructed to avoid alcohol consumption, anti-inflammatory drug use, and exercise 48 h before the blood draws. Serum and plasma were collected and stored at −70°C. All inflammatory marker assays were conducted at the University of Minnesota Cytokine Laboratory. Participants' samples from both time points were analyzed in the same batch and in duplicate. In addition, the same number of control and exercise samples was run in the same batch.
CRP, AA, and leptin were measured in duplicate in plasma by multiplex bead array assays (Millipore, Billerica, MA). Adiponectin was assayed in duplicate in plasma by enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN). Samples were assayed in duplicate and in batches such that each batch contained all samples from each participant and an equal number of exercise and control participants. Two quality control blood samples were included in each batch. Validation studies comparing the multiplex assay with ELISA have shown correlations ranging between 0.83 and 0.93 (10). The intra- and interassay coefficients of variation were 6.2% and 3.4% for leptin, 4.2% and 6.4% for adiponectin, 10.3% and 6.9% for CRP, and 10.3% and 8.5% for AA.
Anthropometrics and body composition.
Body weight was assessed to the nearest 0.1 kg, using an electronic scale (Scale Tronix, White Plains, NY) four times during the study. A stadiometer was used to measure height at baseline without shoes to the nearest 0.1 cm (Scale Tronix). BMI was calculated as the weight in kilograms divided by height in meters squared (kg·m−2). Body composition was measured at baseline and after the intervention by dual-energy x-ray absorptiometry in the total body scanning mode with a Lunar Prodigy DXA apparatus (Lunar Radiation Corp., Madison, WI) at the General Clinical Research Center of the University of Minnesota.
Participants' fitness level was assessed using a submaximal treadmill test at baseline (between days 8 and 12 of menstrual cycle 2) and after the intervention period (between days 8 and 12 of menstrual cycle 6). The protocol involved a 5-min warm-up, followed by a treadmill walk at a steady speed (3.5 miles·h−1), and the grade on the treadmill was increased by 2% every 2 min until the participants reached 80% of HRmax. If a participant was within 10 heart beats of her predicted HRmax, treadmill grade was increased by 1% every 2 min until 80% HRmax was reached. HR during this test was measured using Polar HR monitors (Polar Electro, Inc., Woodbury, NY). This workload was then converted into METs using a standard conversion formula (1).
All participants randomized to the treatment group were asked to keep a workout log to record the date, time and location of workout, type of equipment used, average HR obtained from an HR monitor, duration of workout and stretching, and any comments regarding the workout. Participants were instructed to leave their workout sheets at the gym for weekly checks by the research staff. Adherence was measured in two different ways: by taking the average minute of exercise per week for each of the four stages of exercise and by calculating the percentage of the goal achieved (% goal achieved = (total number of minutes exercised/total number of minutes assigned) × 100) for each stage.
Other study measures.
At baseline, data on demographic information and health history were obtained. Self-reported physical activity before and during study participation was assessed via a modified version of the Modifiable Activity Questionnaire described elsewhere (26). Participants were also asked to complete dietary food records for three consecutive days at baseline and after the intervention. The Food Processor SQL (ESHA Research, Inc., Salem, OR) software was used to calculate nutrient intake. In addition, participants completed the perceived stress scale (7) and the CES-D depression scale (40) at baseline and at the end of the intervention.
Baseline comparisons between controls and exercisers were made using Student's t-test for continuous variables (list variables) and χ2 for categorical variables (BMI, race, ethnicity, education, marital status). Intervention effects were assessed at the end of the intervention (approximately 16 wk) by comparing change from baseline on the inflammatory markers between exercisers and controls as defined at randomization. All participants with baseline and final measurements of inflammatory markers were included in their assigned treatment group (intent-to-treat analysis). All inflammatory markers were log-transformed for analyses. Changes between groups were assessed on the original scale using ANOVA. The overall effects of treatment group on changes in inflammatory markers were adjusted for the stratified randomization by age and BMI.
In the secondary analysis, we examined subgroup effects according to BMI class at baseline, changes in percent body fat (exercisers who lost >2% body fat vs those who did not) and fitness (exercisers who were in the highest quartile of change in fitness (METs > 0.97) vs those in the lowest quartile). Associations between the changes in inflammatory markers and changes in percent body fat and fitness were examined using Pearson correlation coefficients. All P values were adjusted for multiple comparisons using the Tukey test. All analyses were double-sided and performed with SAS software (version 9.2; SAS Institute, Cary, NC).
There were a total of 391 participants randomized into the WISER study, of which 319 successfully completed the study. Of these, 15 and 9 participants were excluded from the CRP and SAA analyses, respectively, because of unusually high levels of SAA or CRP at one of the time points (i.e., >10-fold difference, suggesting an acute inflammatory event). This approach has been previously reported by others (5).
There were no differences in demographic characteristics and other variables between controls and exercisers at baseline (Table 1). Participants were, on average, aged 25 yr and had 36% body fat, and about one-third had a BMI above the reference range (>25 kg·m−2). Likewise, there were no differences between the participants who completed the WISER study and those who dropped out (data not shown).
Overall adherence to the exercise intervention was 92%, and 140 women (86%) exercised for at least 14 wk. Fitness increased by 0.9 METs in the exercise group compared with 0.2 METs in the control group (P < 0.0001). There were no differences in weight change during the study between exercisers and controls (−0.05 ± 0.21 vs +0.39 ± 0.19 kg, P = 0.11). However, the exercise group lost significantly more body fat than the control group (−0.97% ± 0.2% vs −0.11% ± 0.2%, P = 0.0005). Interestingly, calorie intake was significantly lower from baseline in the control group compared with the exercise group (−204 ± 50 vs 22 ± 47 kcal, respectively). No changes in perceived stress or depression scores were observed as a result of the exercise intervention (data not shown).
Overall, 16 wk of aerobic exercise significantly decreased levels of CRP (Table 2), and this effect was largely driven by the effects of exercise on CRP levels of obese participants (Table 3). Obese exercisers had a decrease in CRP levels of −4.38 ± 1.4 mg·L−1 versus an increase of 1.44 ± 1.2 mg·L−1 in obese controls. No changes in AA, leptin, or adiponectin were noted between the two groups.
We also examined the associations between changes in inflammatory markers and changes in fitness and percent body fat, and no associations were found. The levels of all inflammatory markers were not different in exercisers who lost >2% body fat or were in the highest quartile of change in fitness compared with exercisers who did not lose more than 2% body fat and were in the lowest quartile of change in fitness, respectively (Table 4). There were no significant correlations between each one of these markers and changes in percent body fat or fitness (data not shown).
To our knowledge, this is the first large study to examine the effects of aerobic exercise training on several inflammatory markers in women aged 18-30 yr. It is important to study the relationship between exercise and markers of inflammation in younger populations because of the implications for prevention of chronic disease later in life. Although the relationship between inflammatory markers and breast cancer is still unclear, there is a growing body of evidence suggesting a possible link between inflammatory markers and postmenopausal breast cancer (36). Less is known regarding the relationship between inflammatory markers and premenopausal breast cancer.
We found that a 16-wk aerobic exercise program significantly decreased levels of CRP in young women, which was mostly driven by the effects in the obese participants. The effects of 12 wk of exercise training on CRP levels in younger and older adults have been previously reported (44). CRP was significantly decreased in both age groups compared with baseline levels, but no changes in the other inflammatory markers were noted. Similarly, a study examining the effect of 12 months of aerobic exercise on CRP and other inflammatory markers in overweight or obese postmenopausal women found significant decreases in CRP levels only (6). A more recent study showed a trend toward a reduction in CRP levels in predominantly overweight adults (age not specified) after 10 wk of aerobic exercise training (8). Our results support the findings from these studies and suggest that a shorter exercise intervention is sufficient to reduce CRP levels, especially in obese young women. In the HERITAGE study, exercise only decreased CRP in individuals with high baseline levels of CRP (27). Other studies have shown no effects of exercise on CRP levels in various populations (3,5,18,19,22,31). Some of these studies were conducted in patients with underlying medical conditions, which may have altered the effects of exercise on CRP levels; other studies were hampered by small sample sizes, and the duration and intensity of the exercise interventions may also have affected the outcome. Overall, a nonsignificant reduction in CRP levels of approximately 3% was reported in a meta-analysis examining the effects of exercise on CRP in adults (24).
To examine whether the effects of exercise in obese women were mediated, at least partially, by loss of body fat, we further looked into the relationship between changes in percent body fat and changes in CRP levels. Although the exercise group experienced a significant decrease in percent body fat compared with the control group, there was no association between body fat change and CRP levels. This finding has been previously reported in younger and older populations (8,27,37). We also looked at changes in trunk fat as a possible mechanism by which exercise reduced CRP levels based on the findings by Vieira et al. (46), who reported that decreases in CRP with exercise were associated with decreases in trunk fat. In contrast with the study by Vieira et al., we did not find a significant correlation between change in trunk fat and change in CRP. Interestingly, at the end of the intervention, only normal-weight and overweight exercisers had lost trunk fat (−0.41 kg in normal weight and −0.38 kg in overweight exercisers), whereas obese exercisers had gained 0.13 kg of trunk fat. Similarly, we did not find any associations between improvement in fitness and changes in CRP levels, supporting the findings from previous studies (8,27,37). This suggests that the effect of exercise on CRP levels of obese young women is independent of changes in fitness and body composition. We also examined whether the effects of exercise on CRP levels were associated with improvements in stress and depression scores because previous research has shown an improvement of these scores with exercise in older adults (43). However, we did not find any differences between the groups in depression and stress scores, possibly because there were no clinically depressed participants in the study.
Although the mechanism by which exercise may decrease CRP levels is not clear, it has been suggested that exercise may regulate synthesis of ILs and cytokines, by increasing levels of IL-6 and suppressing TNF-α (38). However, there is a lack of clinical evidence that supports this hypothesis. Previous studies have reported no effects of exercise training alone on levels of IL-6 or TNF-α (6,34,44). We did not measure levels of IL-6 and TNF-α in the present study, and therefore, we cannot dismiss the possibility that changes in these cytokines may have led to the observed changes in CRP levels.
No changes in adiponectin levels were observed in the present study, supporting the findings from previous studies including one study conducted in older adults who exercised 4 d·wk−1 during 6 months (23), a 16-wk moderate or intense exercise training in obese middle-aged individuals (31), and a 12-wk exercise intervention conducted with overweight and obese girls aged 9-15 yr (34). Findings from a systematic review suggest that moderate- to high-intensity exercise sessions lasting at least 90 min may be necessary to increase adiponectin levels in adults (42).
Previous studies conducted in obese children, women, and men have reported conflicting results regarding the effects of exercise training on leptin levels (17,25,30). The effects of exercise on leptin levels have been related to changes in weight and/or body fat in previous studies (16,20). The exercise intervention in the present study did not result in weight changes because the study was designed to examine the independent effects of exercise, without concomitant loss of body weight. This may explain the lack of effect on leptin levels. Even when the effect of exercise was stratified by changes in body fat, no changes in leptin levels were found in those who lost >2% body fat compared with those who did not.
We are unaware of previous studies that have examined the effects of exercise on levels of AA in young women. Twelve months of exercise did not change levels of SAA among obese postmenopausal women in a randomized controlled trial (6). The present exercise intervention did not alter levels of AA in women aged 18-30 yr.
Surprisingly, we did not find any significant effects of exercise when we stratified the data by body fat loss or change in fitness. One possible explanation for this was the relatively small changes in percent body fat and fitness observed in the exercise group. As a consequence, there were fewer exercisers who lost >2% of their body fat or were in the upper quartile of change in fitness.
Strengths of the current study include the randomized controlled trial design, the population chosen (young women have not been studied previously in the context of the inflammatory markers measured), the large sample size, the type of exercise intervention, which was based on current public health guidelines for physical activity (45), and the excellent adherence rate. Limitations include the relatively short duration of the exercise intervention and the possible limited generalizability of our findings. Most of the participants in the study were college-aged women not taking any hormonal contraceptives, recruited from the University of Minnesota and a few other colleges in the Twin Cities area. The findings may only be applicable to this specific population. It should be noted, however, that according to the National Center for Education Statistics, 42% of women aged between 18 and 24 yr were enrolled in degree granting institutions in 2007 (35). In addition, it has been estimated that >50% of women aged 20-29 yr do not use hormonal contraceptives (33). It also should be noted that 15 and 9 participants were not included in the CRP and AA analyses, respectively, because of a >10-fold difference between the two measurements. Although choosing a 10-fold difference to exclude participants from the analyses was somewhat arbitrary, based on previous studies of lifestyle modification and changes in CRP levels, we feel that a 10-fold difference can only be a consequence of an acute inflammatory event rather than the effect of an exercise intervention such as the one described in this article. Another aspect of this research that should also be mentioned is that the type of method used to assess CRP levels, which involves the simultaneous analysis of CRP and AA through proprietary bead sets that are specific to each analyte, yields values of CRP that are, on average, 40% higher than those obtained by ELISA (9). This means that reference values for CRP must be revisited and adjusted appropriately should this type of assay be used in clinical settings to assess cardiovascular risk. It must be emphasized that there is good correlation between the two platforms (r = 0.90, P < 0.0001) (9) and that the difference in CRP values between the two should not influence the effects of the exercise intervention described here. The bead-based multiplex assays have several advantages over ELISA, including ability to measure several analytes at once and under a broad range of concentrations, less sample volume needed, cost-effectiveness, ability to perform repeated measures of the same analytes in the same participant under the same experimental assay conditions (29).
Future studies should be aimed at examining the effects of longer exercise interventions on inflammatory markers in obese young adults who may be particularly vulnerable to the later development of chronic diseases given the increasing prevalence of obesity in this age group.
This trial was funded by the National Institutes of Health/National Cancer Institute, U54 CA116849, and National Center for Research Resources, M01-RR00400.
The authors thank Laura M. Turek for the support with recruitment and retention of participants into the WISER study; Alma J. Smith and Maureen O'Dougherty for coordination of the WISER study; Beth Kaufman, Amanda Smock, Holly Jakits, Rachel Wetzsteon, and Dawn Lundin for their assistance with training of the exercise participants; the General Clinical Research Center of the University of Minnesota; the YWCA; and especially the participants for their efforts and cooperation.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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