PDM: Metabolic Syndrome (2013)


Straznicky NE, Lambert EA, Grima MT, Eikelis N, Nestel PJ, Dawood T, Schlaich MP, Masuo K, Chopra R, Sari CI, Dixon JB, Tilbrook AJ, Lambert GW. The effect of dietary weight loss with or without exercise training on liver enzymes in obese metabolic syndrome subjects. Diabetes Obes Metab. 2012; 14(2): 139-148.

PubMed ID: 21923735
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 compare the effects of caloric restriction alone and calorie restriction with moderate-intensity aerobic exercise on liver enzymes in obese metabolic syndrome subjects
  • To identify anthropometric, metabolic, cardiovascular, neuroadrenergic and dietary predictors of changes in liver enzymes following lifestyle interventions
  • To examine he effects of longer-term weight loss maintenance on liver enzymes.
Inclusion Criteria:
  • Men and post-menopausal women
  • Aged 45 to 65 years
  • Overweight or obese
  • Stable body weight (±1kg in the previous six months)
  • Three or more metabolic syndrome criteria (using waist circumference cut-points of 102cm or more for men and 88cm or more for women)
  • Non-smokers
  • Sedentary (physical exercise two or less times per week for less than 20 minutes per session)
  • Willing to accept random assignment
  • Unmedicated (not taking pharmacological agents or dietary supplements)
  • All subjects provided written, witnessed, informed consent.
Exclusion Criteria:
  • History of alcohol consumption of more than 20g per day for females or more than 40g per day for males
  • Prior infection with hepatitis B or C virus or concomitant liver disease
  • Thyroid dysfunction
  • Cardiovascular disease
  • Renal disease
  • Type 2 diabetes.
Description of Study Protocol:


Randomized controlled trial:

  • Stratified randomization by gender and hypertensive status was used to assign subjects to one of three groups:
    • Weight loss by calorie restriction alone (CR)
    • Weight loss by calorie restriction and aerobic exercise (CR+EX)
    • No treatment (control)
  • Subjects who achieved 5% or more reduction in body weight during the intervention phase were offered the option of continuing in a weight management phase.


  • The CR and CR+EX groups received the following dietary intervention:
    • A modified Dietary Approaches to Stop Hypertension (DASH) diet, comprised of 48% energy as carbohydrate, 22% as protein and 30% as fat, of which 9% was saturated, at an energy deficit of 30% (400 to 900kcal per day)
    • Instruction to limit alcohol intake to four or fewer drinks per week
    • 14-day menu plans and recipes and prepared meals in their homes
    • Dietary counseling with the study nutritionist every two weeks
    • Compliance was assessed by prospective four-day diet records, which were analyzed using Australian Food Composition Tables
    • Intervention duration was 12 weeks
  • The CR+EX group received the following exercise intervention:
    • Instruction to ride bicycle for 40 minutes on alternate days at a moderate intensity of 65% of pre-determined maximum heart rate, calculated using the Karvonen formula: 0.65 x (maximum heart rate – resting heart rate) + resting heart rate
    • Workload was increased as necessary to maintain target heart rate
    • Exercise was performed under supervision once a week
    • Remaining sessions were performed at the subjects' homes, using provided exercise bicycles and heart rate monitors
    • Subjects kept records of average heart rate during each exercise session
    • Compliance was assessed by the measurement of maximal oxygen consumption (VO2max, expressed as ml per kg fat-free mass per minute) during a continuous incremental cycle ergometry protocol
    • Intervention duration was 12 weeks
  • Intervention during the weight management phase consisted of:
    • Calorie intake was increased to stabilize energy balance
    • All subjects were encouraged to maintain the DASH diet
    • Subjects previously in the CR+EX group retained their exercise bicycles and continued with their exercise regiment
    • Subjects previously in the CR group received general advice regarding exercise.

Statistical Analysis

  • Two-way repeat measures analysis of variance (ANOVA) was used to test for time effects, group effects and time x group interactions
  • One-way ANOVA was used to compare absolute and relative changes in study parameters
  • The Holm-Sidak test was used for post-hoc comparisons
  • Non-parametric data were log-transformed as appropriate
  • Sub-group analyses by gender were performed by two-way repeat measures ANOVA
  • Proportions were compared by chi-squared test
  • Associations between changes in selected variables were assessed using Pearson's correlations
  • Independent predictors of change in liver enzymes were evaluated by forward stepwise linear regression analysis.
Data Collection Summary:

Timing of Measurements

Anthropometric, metabolic, cardiovascular, neuroadrenergic and dietary variables were measured at baseline and after 12-week lifestyle intervention. Body weight measurements were conducted every two weeks during intervention for the CR group. Body weight and blood pressure measurements were conducted every three weeks during intervention for the CR+EX group.

Dependent Variables

  • Alanine aminotransferase (ALT): Measured by enzymatic nicotinamide adenine dinucleotide (NADH without P-5'-P)
  • γ-Glutamyltransferase (GGT): Measured by L-γ-glutamyl-e-carboxy-4-nitroanilide substrate methods
  • Body weight
  • Body mass index
  • Waist circumference
  • Waist-hip ratio
  • Total body fat mass: Quantified by dual-energy X-ray absorptiometry scans
  • Total body lean mass: Quantified by dual-energy X-ray absorptiometry scans
  • Trunk fat mass: Quantified by dual-energy X-ray absorptiometry scans
  • Abdominal fat L1-L4: A post-hoc assessment was performed by a trained radiographer
  • Leptin: Measured by radio-immuno assay from fasting blood samples
  • Total cholesterol: Measured from fasting blood samples
  • HDL cholesterol: Measured from fasting blood samples
  • LDL cholesterol: Measured from fasting blood samples
  • Triglycerides: Measured from fasting blood samples
  • Fasting glucose: Measured from fasting blood samples
  • Fasting insulin: Measured by radio-immuno assay from fasting blood samples
  • Homeostasis model assessment-insulin resistance (HOMA-IR)
  • Whole-body insulin sensitivity: Calculated from a standard 75g oral glucose tolerance test (OGTT), with blood sampling at zero, 30, 60, 90 and 120 minutes, according to the formula of Matsuda
  • Non-esterified fatty acids (NEFA): Measured by enzymatic colorimetry
  • High-sensitivity C-reactive protein (Hs-CRP): Measured by immunoturbidimetric assay from fasting blood samples
  • Cortisol: Measured by an in-house extracted radio-immunoassay from fasting blood samples
  • Systolic blood pressure: Supine resting blood pressure was recorded as the average of five readings
  • Diastolic blood pressure: Supine resting blood pressure was recorded as the average of five readings
  • Heart rate
  • Whole-body noradrenaline spillover: Noradrenaline was determined by high-performance liquid chromatography with electrochemical detection. A tritiated noradrenaline kinetics study with steady state blood sampling from the brachial artery was used to quantify apparent rates of noradrenaline spillover into and clearance from the central plasma compartment.
  • Cardiac baroreflex sensitivity (BRS): Determined by the sequence method
  • Muscle sympathetic nerve activity (MSNA): Recorded using microneurography. Resting, supine measurements were obtained over a 15-minute period. Recordings were manually analyzed.
  • Maximal oxygen consumption (VO2max): Measured during a continuous incremental cycle ergometry protocol.

Independent Variables

  • Assignment to one of three groups:
    • Weight loss by calorie restriction alone (CR)
    • Weight loss by calorie restriction and aerobic exercise (CR+EX)
    • No treatment (control)
  • Subjects who achieved 5% or more reduction in body weight during the intervention phase were offered the option of continuing in a weight management phase
  • Diet (calories, fat, saturated fat, cholesterol, protein): Diet records were analyzed using Australian Food Composition Tables
  • Exercise training: Subjects kept records of average heart rate during each exercise session.
Description of Actual Data Sample:
  • Initial N: 63 (37 males, 26 females)
  • Attrition (final N): 58
  • Age: 55±6 years
  • Anthropometrics: There were no statistically significant differences between groups.
  • Location: Australia.
Summary of Results:

Key Findings

  • Weight loss averaging 8% to 9% of body weight is accompanied by significant reductions in liver enzymes ranging from 20% to 33%
  • Co-intervention with moderate-intensity aerobic exercise training facilitated greater reduction in central adiposity measures and improved maximal oxygen consumption by 19%, but did not translate to incremental benefits on liver enzyme concentrations or other metabolic and cardiovascular parameters, beyond that attained by weight loss alone.

Change in Anthropometric and Clinical Variables After 12-week Lifestyle Intervention

Variables Control (N=19) Calorie Restriction (N=20) Calorie Restriction + Exercise (N=19) Between Groups (P)
Body weight (kg) 1.0±1.2  −7.1±2.9***,‡  −8.7±4.6***,‡  <0.001 
Body mass index (kg/m2) 0.4±0.4  −2.4±1.0***,‡  −2.9±1.4***,‡  <0.001 
Waist circumference (cm) 1.0±1.2  −6.7±3.2***,‡  −10.0±5.2***, ‡, §  <0.001 
Waist-hip ratio 1.0±1.2  −0.02±0.03***  −0.03±0.03***,‡  0.013 
Total body fat mass (kg) 1.0±1.2  −5.2±3.0***,‡  −7.0±3.9***,‡  <0.001 
Total body lean mass (kg) 1.0±1.2  −1.5±2.1***,‡  −0.7±2.0*,‡  <0.001 
Trunk fat mass (kg) 1.0±1.2  −3.1±2.0***,‡  −4.4±2.8***, ‡, §  <0.001 
Abdominal fat L1 to L4 (kg) 1.0±1.2  −0.5±0.4***,‡  −0.8±0.6***,‡  <0.001 
Leptin (ng per ml) 1.0±1.2  −4.3 (−1.8, −9.0)***,‡  −4 (−1.6, −8.1)***,‡  <0.001 
Total cholesterol (mmol per L) 1.0±1.2  −0.6±0.5***,‡  −0.9±0.6***,‡  <0.001 
HDL cholesterol (mmol per L) 1.0±1.2  −0.07±0.15*  −0.07±0.15*  0.503 
LDL cholesterol (mmol per L)  −0.0±0.5  −0.3±0.4**  −0.4±0.5***,‡  0.035 
Triglycerides (mmol per L)  −0.1 (0.4, −0.5)  −0.3 (0, −0.7)***,‡  −0.7 (−0.2, −1.5)***,‡  <0.001 
Fasting glucose (mmol per L)  0.2±0.4  −0.6±0.7***,‡  −0.7±0.4***,‡  <0.001
Fasting insulin (mU per L)  2.0±5.7  −5.4±5.1***,‡  −2.6±3.4**,‡  <0.001 
HOMA-IR 0.50±1.49  −1.66±1.44***,‡  −0.84±1.0***,‡  <0.001 
Whole-body SI  0.0 (−0.4, 0.3)  0.8 (0.1, 1.6)***,‡  0.7 (0.4, 1.6)***,‡  0.001 
NEFA (mEg per L)  0.00±0.11  −0.04±0.10  0.00±0.18  0.611 
Hs-CRP (mg per L) 0.00±0.11  −0.2 (0.5, −0.6)  −0.4 (0, −1.9)**,†  0.038 
Cortisol (ng per ml)  −15±41  −18±50  −4±35  0.618 
Systolic BP (mm Hg −2.5±11.0  −10.5±9.9***  −10.3±10.5***  0.034 
Diastolic BP (mm Hg)  −0.6±5.3  −3.2±6.0*  −3.6±6.7*  0.255 
Heart rate (bpm)  0.5±4.9  −2.3±7.2*  −4.4±5.5***,‡  0.045 
Cardiac BRS (ms per mm Hg)  −1.9±5.9  3.8±7.0*,†  5.1±6.8**,‡ 0.014 
MSNA (bursts per minute)  −0.9±7.2  −9.9±12.6***,†  −12.7±11.0***,‡  0.009 
MSNA (bursts per 11 hb)  −2.3±9.2  −11.7±21.5**  −19.1±15.3***,‡  0.021
Whole-body noradrenaline spillover (ng per minute 30 (−53, 79)  −61 (−33, −131)***,‡  −108 (−32, −186)**,‡  0.004 
VO2max (ml per minute per kg FFM)  −1.8±3.6  −0.3±4.2  5.1±4.7***, ‡, ††  <0.001 

Values are the mean ±SD or the median (25% and 75%). *P≤0.05, **P<0.01 and ***P≤0.001 vs. baseline; †P<0.05 and ‡P≤0.01 vs. control; §P<0.05 and ††P<0.01 vs. calorie restriction group.


 Correlates of Change in Liver Enzymes After 12-week Lifestyle Intervention

Variables ? Log ALT (U/l) ? Log GGT (U/l)
Δ Body weight (kg) 0.39*  0.37* 
Δ Body mass index (kg/m2 0.40**  0.33* 
Δ Waist circumference (cm 0.030  0.36* 
Δ Total body fat (kg)  0.37*  0.47** 
Δ Abdominal fat mass L1 to L4 (kg)  0.40**  0.55*** 
Δ Trunk fat mass (kg)  0.38*  0.46** 
Δ Peripheral fat mass (kg)  0.28  0.40** 
Δ Log leptin (ng per ml 0.33*  0.37* 
Δ Log whole-body SI  –0.28  –0.46** 
Δ Total cholesterol (mmol per L 0.26  0.32* 
Δ Log hs-CRP (ng per ml)  0.09  0.32* 
Δ Systolic BP (mm Hg 0.32*  0.21 
Δ Diastolic BP (mm Hg)  0.37*  0.38* 
Δ Heart rate (bpm)  0.23  0.41** 
Δ Cardiac baroreflex sensitivity (ms per mm Hg)  *0.41*  -0.44** 
Δ Dietary saturated fat intake % energy  –0.44**  0.12 
g per day 0.35*  –0.02 

*P<0.05, **P<0.01 and ***P<0.001. 

Other Findings

  • Reductions in abdominal fat mass measured at the L1 to L4 region, and in dietary saturated fat consumption, were independently related to changes in liver enzymes during lifestyle interventions
  • Benefits on ALT during active weight loss were retained during the four-month weight loss maintenance phase, whereas GGT levels tended to rebound in conjunction with increases in lipid levels.
Author Conclusion:
  • Moderate weight loss with or without aerobic exercise training favorably influenced liver enzyme concentrations during active lifestyle intervention and longer-term weight loss maintenance in obese subjects with metabolic risk factors
  • Reduction in abdominal fat mass and saturated fat intake were the key drivers of improvement in liver enzymes
  • These findings support current recommendations for weight loss and reduced saturated fat consumption in the management of both metabolic syndrome and non-alcoholic fatty liver disease.
Funding Source:
Government: National Health & Medical Research Council of Australia Project Grant
Diabetes Australia Research Trust Grants
Other: Victorian Government's Operational Infrastructure Support Programme
Reviewer Comments:

Compliance with diet and exercise measured subjectively.  

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? Yes
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? Yes
  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? Yes
  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? Yes
  6.6. Were extra or unplanned treatments described? Yes
  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? Yes
  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)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  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? N/A
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