Effects of exercise combined with caloric restriction on inflammatory cytokines
Journal Title (Medline/Pubmed accepted abbreviation): Appl Physiol Nutr Metab
Year: 2010
Volume: 35
Page numbers: 573-582
doi: 10.1139/H10-046

Summary of Background and Research Design

Background:Chronic inflammation has been implicated in the pathogenesis of several chronic diseases, such as atherosclerosis and diabetes, as well as certain types of cancer. Circulating biomarkers for inflammation such as high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), adiponectin, leptin, and interferon gamma (IFN-γ) are thought to be surrogate markers for chronic diseases. It has been suggested that inflammatory biomarkers may be modified by exercise. However, few laboratory-based studies have assessed the effects of diet and exercise on inflammatory biomarkers in non-obese premenopausal women.

Hypothesis/purpose of study: The authors hypothesized that exercise training combined with caloric restriction would produce favorable changes in circulating inflammatory cytokines, including decreased hs CRP, TNF-α, leptin, and IL-6, and increased adiponectin and IFN-γ concentrations.

Subjects: Of 85 female subjects enrolled in the study, 31 met all screening criteria, and 24 completed the study. At baseline, subjects had mean age of 31.5 ± 0.9 years, mean body mass index of 23.7 ± 0.6 kg/m2, mean percentage of fat mass of 31.7% ± 1.1 %, and mean fat mass of 20.2 ± 1.2 kg.

Experimental design: Normal-to-overweight premenopausal women were enrolled in a controlled exercise, training, and caloric-restriction intervention conducted during 6 consecutive menstrual cycles. The study consisted of a screening period (spanning 1 menstrual cycle), a baseline period (spanning 1 menstrual cycle), 4 intervention periods (spanning 4 menstrual cycles), and a 1-week post-study period. Baseline and post-study assessments of adiponectin, hs-CRP, leptin, TNF-α, IFN-γ, and IL-6 were obtained from single blood samples taken once in the first 7 days of the menstrual cycle. Body mass and composition measurements were also obtained at baseline and after study.

Treatments and protocol:The screening cycle was initiated with the onset of menses and consisted of surveys and questionnaires about medical history, food preferences, allergies, and physical activity, and a prospective determination of the menstrual calendar based on analysis of daily urine samples. The baseline period was initiated at the onset of the next menses and consisted of a complete physical and mental exam, completion of a 3-day diet log, and daily determination of ovulatory status by urinalysis. Subjects also provided a blood sample in the first 7 days of their menstrual cycle after an overnight fast, which was used to determine a complete blood count, a basic chemistry panel, and an endocrine screen. To calculate baseline energy needs and balance, subjects wore a research accelerometer at the hip for 24 hours/day, 7 days/week during days 1 to 7 of the baseline period for assessment of physical activity calories, and had resting metabolic rate (RMR) measured using indirect calorimetry. Daily energy needs supplied to subjects during the study were equivalent to a 20% to 35% reduction in calculated baseline energy values. During the intervention periods, subjects were prescribed dietary intake consisting of 55% carbohydrate, 30% fat, and 15% protein. Subjects exercised 4 times per week via treadmill walking, stationary cycle, and stair stepping, with a workout consisting of a 5-minute warm-up, 40 to 90 minutes of aerobic activity at 79% ± 0.7% maximal heart rate, and a 10-minute cool-down. Subjects expended 13%, 19%, 25%, and 28% of baseline energy needs during intervention cycles 1 to 4, respectively.

Summary of research findings:
  • Mean maximal aerobic activity increased by 8.5 ± 1.7 mL/kg/minute (P < .001) and mean body mass declined 3.7 ± 0.5 kg (P < .001) in response to the intervention.
  • No significant changes in RMR or physical activity energy expenditure were observed in response to the intervention.
  • Significant reductions in circulating IL-6 (0.39 ± 0.04 pg/mL to 0.30 ± 0.03 pg/mL, P .025), IFN-γ (0.58 ± 0.83 pg/mL to 0.42 ± 0.64 pg/mL, P = .030), and leptin (13.18 ± 1.28 pg/mL to 6.28 ± 0.71 pg/mL, P < .001) were detected in response to the intervention.
  • No significant changes in circulating adiponectin, hs-CRP, or TNF-α were observed in response to intervention.

Interpretation of findings/Key practice applications:

The current study reports mixed effects on cytokines after a 4-month exercise and training intervention during which subjects significantly increased aerobic activity and significantly decreased body mass. The reduction in IL-6 might be perceived as beneficial, given its proinflammatory actions, whereas the decrease in IFN-γ may be negative because of the role of IFN-γ in bolstering immunity. The decrease in the adipokine leptin would be expected, given the subjects' loss of body fat. It is not clear if the change in leptin is positive or negative. On one hand, leptin is an antiobesity adipokine and, thus, a decrease might be thought of as bad. However, on the other hand, leptin resistance often accompanies insulin resistance, and decreased leptin might indicate lessening of leptin resistance (a good effect).
It is not clear why the weight loss did not result in changes in adiponectin, hs-CRP, or TNF-α. Like leptin, adiponectin is an adipokine and, with loss of body fat, levels might decline. However, adiponectin is generally associated with positive health effects (eg, increased insulin sensitivity) such as those typically observed in an exercise program, so this is one potential explanation for the maintenance of the adiponectin levels that was observed.
The current study does not help resolve these issues, but does provide an observational assessment of the effect of lifestyle interventions on circulating cytokine levels in healthy, premenopausal, non-obese women. The study is limited by the lack of a control group, the observational design, and possible confounding factors such as self-selection during experimental testing. Additional study arms (eg, no intervention, exercise without caloric restriction) would have provided valuable information on (1) the stability of these biomarkers over time within a given individual who is not undergoing an intervention; and (2) the role of caloric restriction versus exercise in the biomarker changes that were observed. Strengths of the study include the high rate of compliance with the exercise and diet program, the length of the testing period, and the consistent timing in collection of blood samples with respect to subjects' menstrual cycles.
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