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MNT: Weight Management (2015)

Nicklas BJ, Ambrosius W, Messier SP, Miller GD, Penninx BW, Loeser RF, Palla S, Bleeker E, Pahor M. Diet-induced weight loss, exercise, and chronic inflammation in older, obese adults: a randomized controlled clinical trial. Am J Clin Nutr. 2004 Apr; 79 (4): 544-551. PubMed ID: 15051595
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
  • To determine the independent and combined effects of diet induced weight loss and exercise on markers of chronic inflammation by using a single-blind randomized controlled intervention trial in older, overweight and obese men and women with knee osteoarthritis
  • To determine the effects of 18 mo of exercise (EX) and diet-induced weight loss (WL) alone and in combination (WL+EX) on self-reported physical function and disability.
Inclusion Criteria:
Participants must have been:
  • Older (at least 60 years of age)
  • Overweight or obese (body mass index at least 28kg/m2)
  • Sedentary (less than 20 minutes of formal exercise per week for past six months)
  • In the Winston-Salem area.
Exclusion Criteria:
Major or initial exclusion criteria
  • Younger tha 60 years of age
  • Not overweight or obese (BMI at or below 28kg/m2)
  • Not sedentary (more than 20 minutes of formal exercise per week for the past six months).
Screening visit exclusion
Screening visits included a medical history review, physical examination, fasting blood profile and 12-lead resting electrocardiogram to exclude subjects who:
  • Did not have radiographic evidence of tibiofemoral osteoarthritis
  • Did not have knee pain
  • Had contraindications for participation in an exercise program, severe hypertension, recent stroke, chronic obstructive pulmonary disease, type 1 diabetes, psychiatric disease, renal disease, liver disease, active cancer other than skin cancer or anemia
  • Had cognitive impairment (Mini Mental State Examination score of less than 24)
  • Consumed at least 14 alcoholic drinks per week.
Description of Study Protocol:
  • Recruitment: Recruited from the community surrounding Winston-Salem through mass mailings and media advertisements. The subjects were initially screened by telephone for major eligibility criteria before progressing to two screening visits in the Geriatric Research Clinic.
  • Design: Randomized controlled intervention trial
  • Blinding used: Single blinding (all staff involved in data collection were blinded to the treatment assignment of the participants).


  • Four treatment groups:
    • Exercise
    • Diet-induced weight loss
    • Exercise and diet-induced weight loss
    • Control group.
  • Stratified by race: non-Hispanic white or African American
  • Variable block randomization method
  • 18-month intervention divided into three phases:
    • Intensive (Months One to Four)
      • Major emphasis was to heighten awareness of the need to change eating habits to lower energy intake
      • One introductory individual session was followed by 16 sessions (three group sessions and one individual session per month)
      • Each group session included problem-solving, the review of a specific topic and food-tasting of several well-balanced, low-fat, nutritious foods prepared with widely available ingredients
      • The individual sessions were used to review individual progress, solve problems, answer questions and set goals
      • Body weight was measured weekly for both the WL and WL+EX Groups and
        was recorded to the nearest 0.05kg.
    • Transition (Months Five to Six)
      • Eight weeks of biweekly contacts (three group and one individual session)
      • Goals for this phase included:
        • Assisting the participants who had not reached their weight goals to re-establish new goals
        • Maintaining and preventing relapse in the participants who had reached their weight-loss goals.
    • Maintenance (Months Seven to 18)
      • Included monthly meetings and phone contacts every two weeks
      • Newsletters were mailed regularly that provided pertinent nutritional information and notice of upcoming meetings
      • Goals included:
        • Assisting participants who had reached their weight loss goals to maintain their weight loss
        • Providing counsel for participants who had a difficult time losing weight and adhering to the intervention.
  • Adherence to the intervention was based on attendance at scheduled sessions and monthly weight assessments.

Statistical Analysis

  • Performed by using SAS software, version 8
  • Descriptive statistics were calculated for each treatment group (WL, EX, WL+EX and Control) for each assessment (baseline, six months and 18 months)
  • Raw values are reported as means ±SDs unless otherwise indicated
  • Logarithmic transformation of CRP, IL-6, TNF-a, sTNFR1 and sTNFR2 was used to satisfy the model assumptions (normally distributed errors and linear relations): The only cytokine not transformed was IL-6sR
  • Repeated-measures analysis of covariance was used to model each outcome variable separately by using the SAS mixed procedure
  • Since the primary focus was on change, the outcome used was the change from baseline
  • A random effect of subject was included that accounted for the within-subject correlation at the repeated measurements
  • The baseline value of the outcome variable, diet-induced weight loss (yes or no), exercise (yes or no), sex, race (white vs. non-white), follow-up assessment (six vs. 18 months) and baseline BMI were included as fixed effects in the model
  • There was no evidence of a weight loss-exercise interaction (P>0.19 in all cases); thus, no interaction term was included
  • A supplementary analysis included six- and 18-month BMI in the model to assess whether the treatments had an effect above and beyond that explained by a change in BMI
  • To describe the models, adjusted means are reported as means ±SEs for categorical predictors and slopes are reported for continuous predictors
  • Spearman’s rank correlation coefficient was used to examine the relations between change from baseline in cytokines and changes from baseline in BMI at six and 18 months
  • No adjustment for multiple comparisons or for number of variables was made.
Data Collection Summary:

Timing of Measurements

Measurements taken at baseline, six months and 18 months:

  • Body weight was measured and blood was collected in the morning (between 7:00 a.m. and 9:00 a.m.) via venipuncture after the participants had fasted overnight
  • Information concerning comorbid conditions was obtained from a medical history, information on medication use was collected and a physical examination was performed.

Dependent Variables

  • Fasting serum concentrations of IL-6, TNF-a, soluble IL-6 receptor (IL-6sR), soluble TNF-a receptor 1 (sTNFR1), soluble TNF-a receptor 2 (sTNFR2) and CRP were measured by enzyme-linked immunosorbent assays
    • All samples were measured in duplicate and the average of the two values was used for
      data analyses
    • Duplicate samples that did not provide a CV under 15% were re-analyzed and all values were averaged for data analyses
    • All cytokines were measured by using Quantikine immunoassay kits (high-sensitivity for IL-6 and TNF-a) from R&D Systems (Minneapolis)
    • The inter- and intraassay CVs for IL-6 were 7.3% and 3.5%, respectively
    • The inter- and intraassay CVs for TNF-a were 11.8% and 6.2%%, respectively
    • The inter- and intraassay CVs for the soluble receptor assays were less than 5%
    • The inter- and intraassay CVs for the CRP assay (ALPCO, Windham, NH) were 8% and 6.7%, respectively.

Independent Variables

  • Diet program
    • Goal was to produce and maintain an average weight loss of 5% of baseline body
      weight for the duration of the 18-month intervention
    • Subjects were initially counseled to decrease their energy intake by 500kcal per day, thus allowing for a loss of approximately 0.5kg body weight per week.
  • Exercise program
    • The three-day-per-week exercise program consisted of an aerobic phase (15 minutes), a resistance-training phase (15 minutes), a second aerobic phase (15 minutes) and a cool-down phase (15 minutes)
    • The first four months of the 18-month intervention was facility-based. After the first four months, participants who wished to exercise at home underwent a two-month transition phase in which they alternated between the facility and the home
    • After the first four months of facility-based exercise, 64% of the subjects in the two exercise groups remained in the facility-based program, 24% opted for the home-based program and 12% of the subjects chose a combined facility-home-based program
    • The participants were provided with an aerobic exercise prescription that included walking within a heart rate range of 50% to 75% of heart rate reserve
    • The resistance training portion of the program consisted of two sets of 12 repetitions of the following exercises: Leg extension, leg curl, heel raise and step-up
    • Cuff weights and weighted vests were used to provide resistance
    • A one- to 1.5-minute rest interval separated each exercise
    • After two orientation sessions, the participants began with the lowest possible resistance
    • Weight was increased after the participant performed two sets of 12 repetitions for two consecutive days
    • For the participants in the home-based program, weights were exchanged at the participant’s request or after a determination was made to increase weight during face-to-face or telephone contact
    • Telephone contacts were made bi-weekly during the first two months of home-based exercise, tri-weekly during the following two months and monthly thereafter
    • Exercise and attendance logs were used to gather data and monitor progress
    • Exercise compliance was defined as the number of exercise sessions completed divided
      by the total number of prescribed sessions.

Control Variables

  • Control Group
    • Served as a Comparison Group and was designed to provide attention, social interaction and health education
    • Met monthly for one hour for the first three months and discussed topics concerning osteoarthritis, obesity and exercise
    • Question and answer sessions followed each presentation
    • Monthly phone contact was maintained during Months Four to Six and bi-monthly contact was maintained during Months Seven through 18: During each phone contact, information on pain, medications, illnesses and hospitalization was obtained.
Description of Actual Data Sample:

Initial N

316 subjects.

Attrition (Final N)

  • 252 (80%) completed the study (returned for the final data collection visit)
  • Blood was available for analysis from 272 subjects at baseline, 242 subjects at six months and 219 subjects at 18 months
  • Analyses were conducted on data from subjects with a baseline blood sample and at least one follow-up sample.


  Dietary Weight Loss Group Exercise Group Dietary weight loss + Exercise Group Control Group
N 71 67 64 70
Age (years) 68±52 69±6 68±7 69±6


  Dietary Weight Loss Group Exercise Group Dietary weight loss + Exercise Group Control Group
N 71 67 64 70
Non-White (%) 27 20 21 19

Other relevant demographics:

  Dietary Weight Loss Group Exercise Group Dietary weight loss + Exercise Group Control Group
N 71 67 64 70
Women (%) 74 74 74 65
Baseline CRP (mcg/ml) 6.0±6.5 6.8±7.8 6.5±7.9 5.9±6.0
Baseline IL-6 (pg/ml) 4.7±3.4 4.4±3.1 4.9±3.0 4.7±3.2
Baseline IL-6sR (pg/ml) 35,197±8,911 34,581±9,596 35,156±11,075 38,040±10,764
Baseline TNF-a (pg/ml) 2.5±1.8 3.4±4.8 3.4±6.4 3.8±7.5
Baseline sTNFR1 (pg/ml) 1,409±470 1,433±404 1,395±397 1,464±421
Baseline sTNFR2 (pg/ml) 2,674±842 2,760±807 2,656±792 2,850±1,127


  Dietary Weight Loss Group Exercise Group Dietary weight loss + Exercise Group Control Group
N 71 67 64 70
Baseline Body Weight (kg) 95.6±15.2 92.4±14.6 91.8±17.4 95.7±18.8
Baseline BMI (kg/m2) 34.4±4.9 34.6±5.8 33.9±5.6 34.5±5.3


Winston-Salem, NC.


Summary of Results:

Key Findings

    N Change BMI
Spearman's correlation coefficient
Change CRP Six months 242 0.11 0.08
18 months 214 0.07 0.30
Change IL-6 Six months 229 -0.06 0.36
18 months 208 0.00 0.95
Change IL-6sR Six months 231 0.04 0.59
18 months 210 -0.12 0.09
Change TNF-a Six months 232 0.16 0.02
18 months 210 -0.06 0.40
Change sTNFR1 Six months 240 0.25 <0.0001
18 months 219 0.18 0.007
Change sTNFR2 Six months 240 0.18 0.006
18 months 219 0.11 0.10

Other Findings

  • Subjects in the WL Group lost 5.7% of their baseline body weight and reduced their BMI by 2.0 during the 18-month intervention
  • Subjects in the WL+EX Group lost 4.4% of their baseline body weight and reduced their BMI by 1.48 (P<0.0001 relative to the Control Group)
  • Body weight did not change significantly in the EX Group (-2.6%) relative to the Control Group (-1.3%).

C-Reactive Protein

  • CRP concentrations decreased more in subjects in the WL Group than in subjects who did not undergo weight loss (i.e., those in the EX and Control Groups): Change in delta log CRP, -0.26±0.07mcg compared with 0.04±0.07mcg per ml; P=0.01
  • There was a significant effect of sex, such that CRP decreased more in men than in women (delta log CRP, -0.29±0.09mcg compared with -0.02±0.06mcg per ml; P=0.0062), but there was no significant effect of race (P=0.88).

Interleukin 6 and Soluble Interleukin 6 Receptor

  • There was a significant main effect of WL (P=0.009) but not EX (P=0.86) on changes in IL-6 concentrations: IL-6 concentrations decreased more in subjects in the WL Group than in subjects who did not undergo weight loss (delta log IL-6, -0.13±0.04pg compared with -0.01±0.04pg per ml)
  • There was an overall effect of race: IL-6 concentrations decreased more in non-white than in white subjects (delta log IL-6, -0.13±0.06pg compared with -0.01±0.03pg per ml; P=0.042)
  • There was a marginally significant racial difference, however, IL-6sR concentrations decreased more in non-white than in white subjects (delta log IL-6sR, -2,205±747pg compared with -639±367pg per ml; P=0.055)

Tumor necrosis factor a and soluble tumor necrosis factor receptors

  • In the WL Group, TNF-a concentrations decreased more in non-white than in white subjects (delta log TNF-a, -0.20±0.08pg compared with -0.01±0.04pg per ml; P =0.017)
  • Diet-induced WL resulted in a significant reduction in sTNFR1 concentrations, compared with no WL (delta log sTNFR1, -0.070±0.017pg compared with -0.013±0.017pg per ml; P=0.007)
  • sTNFR1 concentrations decreased more in non-white than in white subjects (delta log sTNFR1, -0.084±0.02pg compared with 0.002±0.01pg per ml; P=0.001)
  • There was a marginally significant racial difference: sTNFR2 concentrations decreased more in non-white than in white subjects (delta log sTNFR2, -0.046±0.02pg compared with 0.001±0.01pg per ml; P=0.07).

Ratios of cytokines to cytokine receptors

There were no significant effects of WL, EX, sex or race on IL-6/IL-6sR, TNF-a/sTNFR1, TNF-a/sTNFR2 or TNF-a/R1+R2, except that race was significant at 0.0494 as a predictor of TNF-a/sTNFR2 (with white subjects having higher ratios).

Association between changes in BMI and changes in markers of inflammation

Changes in the soluble TNF-a receptors but not in CRP or other cytokines correlated directly with changes in BMI.

Secondary analysis showed

  • BMI was marginally significant (beta=0.029, P=0.057) as a predictor of CRP concentrations, but there was still a significant effect of WL on changes in CRP (P=0.020).
  • BMI was not a significant predictor of IL-6 concentrations (beta=-0.004, P=0.60) and there was still a significant effect of WL (P=0.008)
  • BMI was a strong predictor of sTNFR1 concentrations (beta=0.0092, P=0.007), but there was still a significant effect of WL (P=0.019).
Author Conclusion:
  • The results of the present randomized controlled trial in older, obese men and women with knee osteoarthritis showed that 18 months of a dietary weight-loss intervention reduced circulating concentrations of CRP, IL-6 and sTNFR1
  • Except for sTNFR1, the effect of the intervention was independent of changes in body weight
  • Additional studies with larger sample sizes are needed to explore the possibility of sex and race differences in the response of these inflammatory biomarkers to weight loss
  • In addition, more trials are needed to assess the effects of different modes and intensities of exercise on inflammation.
Funding Source:
University/Hospital: Wake Forest University Claude D Pepper Older Americans Independence Center from the National Institute of Aging (P60 AG10484) and Wake Forest University School of Medicine General Clinical Research Center (M01-RR00211)
Reviewer Comments:
Delta symbol is not available in this program and thus the word is spelled out.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? ???
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? No
  6.6. Were extra or unplanned treatments described? No
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes