This study found that a 12-month caloric restriction weight loss diet intervention, with or without exercise, produced large, significant reductions in several biomarkers of inflammation. This trial tested a caloric restriction diet intervention consistent with the recommendations of the NIH Obesity Education Initiative Expert Panel (calorie reduction of 500–1000 kcal/day), and an exercise intervention consistent with federal guidelines for physical activity (30–45 minutes/day of moderate or greater intensity activity, ≥5 days/week) (43
). Our caloric restriction diet intervention groups experienced mean weight losses of 9–11% (33
). The exercise and diet+exercise groups, respectively completed mean (SD) 163.3 (70.6) and 171.7 (62.7) minutes/week of moderate-to-vigorous intensity activity (target 225 minutes/week). These results suggest that modest amounts of weight loss can have large beneficial effects on clinically-relevant inflammatory biomarkers, which could impact risk reduction of several cancers in overweight or obese, postmenopausal women.
A systematic review of 33 intervention studies has shown that each 1kg of weight loss corresponds to 0.13 mg/L reduction in CRP (20
). The mean weight loss in our diet+exercise group was 8.9 kg. The expected mean reduction of 1.157 mg/L in CRP is consistent with our observed mean reduction of 1.05 mg/L ([hs-CRP outliers ≥20 mg/L, N=2] were removed from this estimate).
A small number of studies have investigated the long-term (12 months or more) combined and independent effects of dietary weight loss and exercise on inflammatory biomarkers. In an 18-month randomized controlled trial among 316 older (≥60 years old), overweight or obese adults with knee osteoarthritis, dietary weight loss with or without exercise, but not exercise-alone, reduced CRP and IL-6 particularly in men (21
), similar to the findings in our study. Another 12-month randomized controlled trial comparing individual and combined effects of low-fat diet and/or exercise programs among 274 adults found that diet with or without exercise significantly reduced CRP only among postmenopausal women with metabolic syndrome (23
In our study, higher adherence to the caloric restriction diet intervention, whether measured by weight loss, session attendance, or reduction in percent calories from fat, was associated with greater reductions in hs-CRP. Conversely, no associations were observed between exercise adherence and inflammatory biomarkers. Direct comparisons of diet vs. no diet groups showed significant reduction in all inflammatory biomarkers in the diet groups.
We found that hs-CRP decreased to the greatest degree in women who lost ≥5% of baseline weight regardless of intervention group. Trials testing lifestyle interventions to produce weight loss in other populations, including persons with impaired glucose tolerance, type 2 diabetes, and premenopausal women, have found significant correlations between changes in BMI and inflammatory biomarkers (e.g., CRP, IL-6) over 1–2 years (22
Previous meta-analyses and reviews support a lack of effect of either short- or long-term aerobic exercise on inflammatory biomarkers in the absence of weight loss (28
). Among 115 overweight or obese postmenopausal women, we found significant linear trends of greater weight loss associated with a larger decrease in CRP during a 12-month exercise trial in which exercisers attained a mean 171 minutes/week (30
). Similarly, a 6-month trial designed to test exercise dose (70–120 minutes/week) on CRP in 464 overweight and obese postmenopausal women found that exercise decreased mean CRP only in women with ≥2.6 kg weight loss (28
There is little information on long-term effects of other types of exercise on inflammatory biomarkers. Two randomized clinical trials showed measureable declines in CRP over 4–12 months with resistance exercise compared with controls in diabetic men (48
) or in premenopausal women (49
). Therefore, the effects on inflammatory biomarkers of resistance training alone or combined with aerobic exercise, in postmenopausal women are unknown.
Representative population data show positive associations between adiposity and leukocyte counts (50
). To our knowledge, our study is the first investigation reporting long-term (12 months) effects of a caloric restriction weight loss diet with and without exercise on leukocyte and neutrophil counts. Leukocyte and neutrophil counts decreased in the diet and diet+exercise, but not exercise, groups. We also found reduced leukocyte and neutrophil counts among individuals who lost ≥5% of initial weight in the diet+exercise groups. However, leukocytes and neutrophil counts reduced in women with <5% weight loss in the diet group. Future studies are required to understand effects and underlying mechanisms of caloric restriction weight loss diet and exercise interventions on leukocyte and neutrophil counts.
We found no difference in intervention effects on inflammatory biomarkers in statin users and nonusers. A meta-analysis of 65 statin intervention studies concluded that statin reduced CRP by 30.8% (95%CI=22.3–39.4%) (15
). In our study, women in the diet and diet+exercise groups decreased hs-CRP by 36–42%, similar to the highest impact of statins. In addition, these women significantly reduced hs-CRP independent of statin use at baseline, consistent with results from the LookAHEAD trial in type 2 diabetes patients (22
). Our results suggest that weight loss through a caloric restriction diet with or without exercise could have additive effects on pharmacological treatments for reducing inflammation.
Our observed 40% reductions in hs-CRP in the diet and diet+exercise groups could be expected to reduce breast, endometrial and other cancer risks in postmenopausal women. A meta-analysis of 8 case-control and 6 cohort studies concluded that each log unit increase in CRP was associated with increase in overall cancer risk (random effects risk estimate=1.10, 95%CI=1.02–1.18) and lung cancer risk (random effects risk estimate=1.32, 95%CI=1.08–1.61) (11
). In a cohort of 4209 women aged 55 years and older, women with CRP levels between 3–10 mg/L had a 60% increased risk of breast cancer (hazard ratio=1.59, 95%CI=1.05–2.41) compared with those with CRP <1 mg/L (9
). A nested case-control study within the Women’s Health Initiative observational cohort found that non-hormone users in the highest CRP quartile (>3.33 mg/L) had a greater than doubling of risk (hazard ratio=2.29, 95%CI=1.13–4.65) for endometrial cancer compared to women in the lowest CRP quartile (<0.64 mg/L) (12
Strengths of this study include: a large sample size, a randomized controlled trial design, three intervention arms, long duration of the intervention (12 months), high retention (91%), high adherence to intervention prescriptions, and multiple measures of inflammation.
There were several limitations. Our study sample was highly selected (e.g., inclusion criteria and intervention requirements) which may limit the generalizablity. The trial sample of overweight and obese postmenopausal women was relatively homogeneous sample, which may limit the generalizability for other race or ethnic groups, for normal-weight or younger women, or for men. However, our sample represents a large segment of the population who are at increased risk for several cancers. We tested only one dietary weight loss program and one exercise program, and therefore cannot extend results to other dietary patterns or exercise modalities. However, our diet intervention was based on the known weight loss efficacy of the Diabetes Prevention Program (37
) and Look AHEAD interventions (38
). Thus, our findings provide critical evidence on the benefits of weight loss and exercise lifestyle change interventions for reducing inflammatory biomarkers in postmenopausal women.
In conclusion, our findings support weight loss through calorie reduction and increased exercise as a means for reducing inflammatory biomarkers, and thereby potentially reducing cancer risk in overweight and obese postmenopausal women.