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J Intern Med. 2013 August ; 274(2): 163–175. doi:10.1111/joim.12062.
Effects of individual and combined dietary weight loss and

exercise interventions in postmenopausal women on
adiponectin and leptin levels
Clare Abbenhardt, MSc1,2, Anne McTiernan, MD, PhD*,2,6,8, Catherine M. Alfano, PhD3,
Mark H. Wener4, Kristin L. Campbell, PhD5, Catherine Duggan, PhD2, Karen E. Foster-
Schubert, MD6, Angela Kong, PhD2,11, Adetunji T Toriola, MD, PhD1,7, John D. Potter, MD,
PhD2,8,9, Caitlin Mason, PhD2, Liren Xiao, MSc2, George L. Blackburn, MD, PhD10, Carolyn
Bain, MSc2, and Cornelia M. Ulrich, PhD*,1,2,8
1Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer
Research Center, Heidelberg, Germany 2Division of Public Health Sciences, Fred Hutchinson
Cancer Research Center, Seattle, WA, USA 3Office of Cancer Survivorship, National Cancer
Institute/National Institutes of Health, Bethesda, MD, USA 4Department of Laboratory Medicine,
University of Washington, Seattle, WA, USA 5Faculty of Medicine, University of British Columbia,
Vancouver, BC, Canada 6School of Medicine, University of Washington, Seattle, WA, USA
7Department of Surgery, Division of Public Health Sciences and Siteman Cancer Center,
Washington University School of Medicine, St. Louis, MO, USA 8School of Public Health,
University of Washington, Seattle, WA, USA 9Centre for Public Health Research, Massey
University, Wellington, New Zealand 10Division of Nutrition, Harvard Medical School, Boston, MA,
USA 11Cancer Education and Career Development Program, University of Illinois at Chicago,
Chicago, IL, USA
Abstract
Background—Excess body weight and a sedentary lifestyle are associated with the development
of several diseases, including cardiovascular disease, diabetes, and cancer in women. One
proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived
adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss
and exercise interventions on adiponectin and leptin concentrations.
Methods—Overweight/obese postmenopausal women (n=439) were randomized as follows: 1) a

reduced calorie, weight loss diet (diet; N=118); 2) moderate-to-vigorous intensity aerobic exercise
(exercise; N=117); 3) a combination of a reduced calorie, weight loss diet and moderate-to-
vigorous intensity aerobic exercise (diet+exercise; N=117); or 4) control (N=87). The reduced
calorie diet had a 10% weight loss goal. The exercise intervention consisted of 45 minutes of
moderate-to-vigorous aerobic activity 5 days/week. Adiponectin and leptin levels were measured
at baseline and after 12 months of intervention using a radioimmunoassay.
Copyright : CTA A
Corresponding Author:neli.ulrich@nct-heidelberg.de.
*These authors are dual senior authors
Financial Disclosures: None reported.
Conflicts of Interest: None for Clare Abbenhardt, Catherine M. Alfano, Mark H. Wener4, Kristin L. Campbell, Catherine Duggan,
Karen E. Foster-Schubert, Angela Kong, Adetunji T Toriola, John D. Potter, Caitlin Mason, Liren Xiao, George L. Blackburn,
Carolyn Bain, Cornelia M. Ulrich Anne McTiernan: Consultant for Metagenics (minor); Merck stock (minor)
Abbenhardt et al. Page 2
Results—Adiponectin increased by 9.5 % in the diet group and 6.6 % in the diet+exercise group
(both p≤0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet
+exercise, −40.1%, p<0.0001; diet, −27.1%, p<0.0001; exercise, −12.7%, p=0.005). The results
were not influenced by the baseline body mass index (BMI). The degree of weight loss was
inversely associated with concentrations of adiponectin (diet, p-trend=0.0002; diet+exercise, p-
trend=0.0005) and directly associated with leptin (diet, p-trend<0.0001; diet+exercise, p-
trend<0.0001).
Conclusion—Weight loss through diet or diet+exercise increased adiponectin concentrations.
Leptin concentrations decreased in all of the intervention groups, but the greatest reduction
occurred with diet+exercise. Weight loss and exercise exerted some beneficial effects on chronic
diseases via effects on adiponectin and leptin.
Keywords
adiponectin; leptin; randomized controlled trial; diet and exercise intervention
Background
Being overweight or obese, and having a sedentary lifestyle may account for as much as
80% of the most common chronic diseases, including cardiovascular disease, hypertension,
cancer, and type 2 diabetes [1]. Obesity is a risk factor for cardiovascular disease, and is
associated with an increased risk of morbidity and reduced life expectancy [2]. In addition,
obesity drives diabetic and vascular mortality [3, 4]. Higher levels of regular, moderate-
intensity physical activity are associated with a reduced risk of several cancers, including
cancers of the breast, colon, and endometrium [5, 6]. Prospective studies suggest that
women who lose weight and maintain the weight loss experience a reduction in breast
cancer risk [6-9]. Although the biologic mechanisms that mediate the association of obesity,
sedentary lifestyle, and weight loss with cancer risk and other chronic diseases are not fully
understood, alterations in hormone signaling, especially insulin, sex steroids, and adipokine
pathways, may play an important role [10, 11].
Adipose tissue cells secrete several metabolically-active peptides and proteins, among which
are adiponectin and leptin. Adiponectin is an insulin-sensitizing, anti-angiogenic, anti-
inflammatory hormone that plays a central role in energy homeostasis, as well as lipid and
glucose metabolism [12, 13]. The serum concentrations of adiponectin have been described
as a positive predictor of all-cause cardiovascular mortality in patients with type 1 diabetes,
and could potentially be implemented as a biomarker for diabetes [14, 15]. Leptin is a key
regulator of appetite, food intake, and body weight. Leptin is also an important factor in
energy homeostasis, metabolism, and adiposity [16, 17].
The effects of long-term (≥1 year) dietary weight loss in postmenopausal women by diet
alone and exercise or diet and exercise combined on adiponectin and leptin levels have yet
to be clearly established. The serum leptin concentration increases with weight gain and
decreases with short-term diet-induced weight loss [18, 19]. The adiponectin concentration
is inversely correlated with adiposity, although the impact of weight loss is unclear [20, 21].
The role of exercise on adipokines is also unclear. In a randomized controlled trial involving
320 postmenopausal women, a year-long aerobic exercise intervention (225 minutes/week)
was associated with increased adiponectin and decreased leptin concentrations [22];
however, another study showed that the effect of a hypocaloric diet and/or aerobic exercise
in 40 overweight and obese postmenopausal women did not result in a change in adiponectin
concentrations with a moderate weight-reduction program or exercise regimen [9].

The present randomized controlled trial investigated the independent and combined effects
of a reduced calorie diet and a moderate-to-vigorous aerobic-exercise intervention on
circulating adiponectin and leptin concentrations in postmenopausal women. Our hypothesis
was that a reduced calorie, weight loss diet with moderate-to-vigorous aerobic exercise
would produce a greater increase in the adiponectin level and a greater reduction in the
leptin concentration than either intervention alone, and compared to no lifestyle change
(control). We hypothesized that the intervention effects on adiponectin and leptin levels
would be stronger in women who were obese at baseline with a greater degree of weight or
body fat loss during the intervention.
Subjects and Methods

Study Design and Participants
The Nutrition and Exercise for Women (NEW) study was a 12-month randomized
controlled trial, conducted between 2005 and 2009, which tested reduced calorie dietary
weight loss and exercise effects on biomarkers of postmenopausal breast cancer risk and
other endpoints [23, 24]. Participants were recruited from the greater Seattle area
(Washington, USA) through mass mailings, media placements, and community outreach.
Inclusion criteria were as follows: 50-75 years of age; BMI ≥25.0 kg/m2 (if Asian-
American, ≥23.0 kg/m2); <100 minutes of moderate activity/week; postmenopausal; no
menopausal hormone therapy for the past 3 months; no history of breast cancer, heart
disease, diabetes mellitus, or other serious medical conditions; fasting glucose <7.0 mmol/L
and not taking diabetic medications; non-smoking; alcohol intake of <2 drinks/day; ability to
attend diet/exercise sessions at the intervention site; and a normal exercise tolerance test.
The trial design and recruitment (Figure 1) have been previously reported [23]. Briefly, a
total of 439 eligible women were stratified according to BMI (<30 kg/m2 or ≥30 kg/m2) and
race/ethnicity (non-Hispanic White, Black, other), then randomized into one of four groups:
1) reduced calorie, weight loss diet (diet; N=118); 2) moderate-to-vigorous intensity aerobic
exercise (exercise; N=117); 3) combined reduced calorie, weight loss diet and moderate-to-
vigorous intensity aerobic exercise (diet+exercise; N=117); or 4) no diet or exercise change
(control; N=87).
We used permuted-block randomization (ratio 0.75:1:1:1) to assign a proportionally smaller

number of women to the control group. The Fred Hutchinson Cancer Research Center
(FHCRC) Institutional Review Board in Seattle approved the study, and all participants
signed informed consent.
Interventions and Control Group

The reduced calorie, weight loss intervention was a modification of the Diabetes Prevention
Program [25] and the Look AHEAD [26] lifestyle interventions, and has been previously
described [23]. The diet had a total energy intake goal of 1200-2000 kcal/day based on
weight and <30% daily energy intake from fat. The weight loss goal was 10% by 6 months,
with maintenance thereafter. Dietitians with training in behavior modification conducted
sessions. Participants met individually with a study dietitian at least twice and attended
weekly dietitian-led group meetings (5-10 women) in months 1-6. In months 7-12,
participants attended monthly group meetings, in addition to phone or email contact with the
dietitians. The diet+exercise group diet sessions were held separately from those of the diet
group and participants were requested not to discuss diet during facility drop-in exercise
training sessions.

The exercise intervention goal was 45 minutes of moderate-to-vigorous intensity exercise 5

days/week for 12 months. Participants attended three supervised sessions/week at the facility
and exercised 2 days/week at home. The participants gradually increased exercise training to
70-85% of the observed maximal heart rate by the 7th week, and maintained that intensity of
exercise for the duration of the study.
Women randomized to the control group were asked not to change their diet or exercise
habits. After 12 months, women were offered four weight loss classes and 8 weeks of
facility exercise training.
Measures
The primary outcomes for the present analyses were serum concentrations of adiponectin
and leptin. We collected 12-hour fasting serum at baseline and 12 months. The samples were
processed within 1 hour and stored at −70°C. Laboratory assays were performed at the
Northwest Lipid Research Laboratory at the University of Washington on 438 baseline
samples (1 blood sample was missing) and 399 (vide infra) 12-month follow-up samples.
Adiponectin was measured by a commercially available radioimmunoassay (Millipore Inc.,

Billerica, MA, USA) using 125I-labeled murine adiponectin as a control and a multispecies
anti-adiponectin antibody. The assay has a sensitivity of 1 ng/mL. Serum analyses were
performed in duplicate and the results reported as the mean of the two values. The intra- and
inter-assay coefficients of variation (CV) were 8.4% and 9.8%, respectively.
Leptin assays were performed with a commercially available radioimmunoassay (Millipore

Inc.) using125I-labeled human leptin and a human leptin antiserum to determine the level of
leptin by the double antibody/PEG technique. The sensitivity of this assay is 0.5 ng/mL.
Each sample was analyzed in duplicate. The intra- and inter-assay CV were 9.1% and
14.3%, respectively.
We assessed demographics, medication use, lifestyle behaviors, and anthropometrics at

baseline and 12 months. Height and weight were measured with a stadiometer and standard
scale, respectively, and BMI was calculated as kg/m2. Body fat was measured using a DXA
whole-body scanner (GE Lunar, Madison, WI, USA).
Statistical Analysis
Descriptive data are presented as the mean ± SD. Blood measures were log-transformed to
compensate for the skewed distribution in the original measures. Accordingly, geometric
means with 95% confidence intervals (CI) are presented. We examined the intervention
effects on an intent-to-treat basis. The mean 12-month changes in the diet, exercise, and diet
+exercise groups were compared to controls and to the other intervention groups using the
generalized estimating equations (GEE) approach to random-effects regression; this
accounted for the correlation within each individual over time [23]. We used the Bonferroni
correction (two-sided alpha=0.05/6; critical p-value of p<0.0083) to adjust for multiple
comparisons.
We assessed changes in adipokines for each intervention group using GEE models by pre-
planned subgroups: 1) BMI (obese vs. non-obese: <30 and ≥ 30 kg/m2) [27]; 2) weight loss
(using cut points previously shown to reduce metabolic risk factors for diseases, such as
diabetes: <5%, 5-10%, and ≥ 10%) [28]; 3) body fat loss (tertiles, ≤2.58%, 2.58-6.35%, and
>6.35%). For the subgroup analyses, p<0.05 was considered statistically significant. We
used SAS software (version 9.1; SAS Institute, Cary, NC, USA) to perform all statistical
analyses.

Results
The mean age of the participants was 58.0 ± 5.0 years. The majority of participants were
non-Hispanic whites and highly educated (60% had a college degree or higher; Table 1).
Three hundred ninety-nine (91%) of the randomized participants returned for a 12-month
blood draw; there were no significant differences across the intervention groups (Figure 1).
Approximately 42% (N=49) of women assigned to the diet group and 60% (N=69) of those
in the diet+exercise group achieved the goal of a 10% reduction in weight over the 12-month
period. The diet+exercise group completed 80% of the exercise goal (225 minutes/week),
and the exercise group completed 85% of the exercise goal (data not shown).
At the end of the 12-month intervention period, there were improvements in all measures of
adiposity in the three intervention groups compared to the control group. The most marked
changes were in the diet+exercise group [23]; specifically, weight decreased by 10.8%
(p<0.01), whereas the reductions in weight in the diet and exercise groups were 8.5%
(p<0.01) and 2.4% (p=0.08), respectively. Compared with controls, the largest decrease in
body fat was observed in the diet+exercise group (−5.9%), the least reduction in body fat
occurred in the exercise group (−1.7%), and the diet group lost −4.3% body fat (all
p<0.021).
The diet+exercise (6.6%) and diet groups (9.5%) had statistically significant increases in the
mean serum adiponectin concentrations compared with controls (p<0.0001; Table 2). In
contrast, the mean adiponectin concentrations decreased by 2.6% and 3.3%, respectively,
among women in the exercise and control groups. In the diet+exercise group, there was a
mean 40% decrease in the leptin concentration compared to the control group (p<0.0001).
Statistically significant reductions in leptin concentrations also occurred in the diet (27%,
p<0.0001) and exercise groups (13%, p=0.005). The difference in leptin level change
between the diet and diet+exercise intervention groups was statistically significant
(p=0.0003); this was not the case for adiponectin (p=0.32).
Table 3 shows analyses stratified by BMI categories (<30 kg/m2 and ≥30 kg/m2). Among
women randomized to the diet intervention, the serum adiponectin concentration increased
in both BMI categories. Although the increase was more pronounced in participants with a
BMI <30 kg/m2 (14.1% for a BMI < 30 kg/m2 vs. 3.3% for a BMI ≥ 30 kg/m2), the
difference between the two groups was not statistically significant. The leptin concentration
decreased in both BMI categories in the diet and diet+exercise groups, and to a lesser extent
in the exercise group.
When stratified by percent weight loss (Table 4), women in the diet+exercise and diet
groups with the greatest weight loss (>10%) had statistically significant increases in
adiponectin (+11.7%; p=0.047 and +18.5%; p=0.02, respectively) compared to controls. The
amount of weight loss from baseline was directly related to the increase in adiponectin (diet,
p-trend<0.002; diet+exercise, p-trend<0.005) and the reduction in leptin across the weight
loss categories (diet, p-trend<0.0001; diet+exercise, p-trend<0.0001).
Stratification by body fat loss revealed similar patterns (Figure 2 and Supplementary Table
1) of statistically significant changes in adiponectin and leptin concentrations among
participants in the intervention groups compared to controls. Because four levels of fat loss
were investigated, and the control group showed few body fat changes, the comparisons
were made in relation to the entire control group. In all three intervention groups, women
with higher percent body fat changes experienced greater mean changes in adiponectin and
leptin concentrations. Trends towards increasing adiponectin levels among participants
losing more fat were highly significant for participants in the diet group (p-trend <0.0001).

Reductions from 47.1% (exercise) to 55.3% (diet+exercise; both p=0.0001) were observed
among participants who lost > 6.35% body fat compared to controls.
An evaluation of the effects of the interventions on adipokines stratified by BMI is presented

in Supplementary Table 2.
Discussion
This randomized controlled trial among healthy overweight and obese postmenopausal
women compared the individual and combined effects of a 12-month reduced calorie dietary
weight loss intervention, with or without exercise, on serum adiponectin and leptin
concentrations. We observed substantial reductions in leptin concentrations in the three
intervention groups, with the largest reduction (40%) among women in the diet+exercise
group. Adiponectin concentrations increased among women in the diet+exercise and diet
groups, but not among women in the exercise group. Regardless of the intervention, weight
loss had a dose-dependent effect on leptin and adiponectin levels. The greatest increase in
adiponectin levels and decrease in leptin levels occurred in participants in the diet and diet
+exercise groups, who lost ≥10% of baseline weight or > 6.35% of body fat. The largest
increase in adiponectin level approached 20% (diet group) and the largest decrease in leptin
level was > 55% (diet+exercise group).
To date, randomized trials have tested the effect of weight loss on adiponectin and leptin
levels, using hypocaloric diets and diets that differ in macronutrient composition [29, 30].
Summer et al. [29] reported that the adiponectin level increased with a low-carbohydrate,
but not a low-fat, diet, with no correlation between weight loss and increase in adiponectin
concentrations. In a 6-month weight loss intervention study with dietary weight loss and
resistance training in 46 healthy postmenopausal women, Drapeau et al. [31, 32] reported
that a 7.7% weight loss in the caloric restriction group led to a 4.9% increase in adiponectin,
while an 8.2% weight loss in the combined group led to a 12.8% rise in the serum
adiponectin level.
The literature varies on the effect of exercise alone on adiponectin and leptin levels. Several
randomized controlled trials have shown no relationship between exercise and changes in
adiponectin concentrations, although there is some evidence that moderate- or high-intensity
resistance training produces body composition changes that reduce circulating adiponectin
concentrations [33]. Friedenreich et al. [22] reported that a year-long aerobic-exercise
intervention (225 minutes/week) led to an 18.9% reduction in leptin levels in 320 previously
inactive postmenopausal women, but no differences in adiponectin concentrations existed
between exercisers and controls. In the current study, exercise alone had no effect on the
adiponectin level and there was a modest effect (~13% reduction) on the leptin level. In an
identical exercise intervention to that of the current study, Frank et al. [34] reported that 12
months of moderate-intensity aerobic activity, 5 days/week for 45 minutes, resulted in a 7%
reduction in leptin concentrations in postmenopausal women.
The results from our study are similar to the results reported by Christiansen et al. [30], in
which 79 obese males and females were randomized to a hypocaloric diet with or without
aerobic-exercise training using a 3-group trial (diet, diet+exercise, and exercise). In that
study, the diet and diet+exercise groups lost a mean of 12.3 kg and the exercise group lost a
mean of 3.5 kg over 12 weeks. There was a statistically significant increase in serum
adiponectin concentrations in the diet and diet+exercise interventions, but not in the exercise
group [30]. In addition, the Diabetes Prevention Program (DPP), which included a lifestyle
group that prescribed a reduced calorie weight loss program and increased physical activity,
showed an increase in adiponectin after 1 year in the lifestyle (diet+exercise) group [35].

Our diet intervention was based on the DPP lifestyle intervention, and had outcomes
consistent with the DPP findings. Overall, our data and the data from other studies suggest
that weight loss and/or reduction in body fat might be triggers for increases in adiponectin
concentrations.
Our large sample size enabled us to investigate intervention effects stratified by several
measures of body composition. We hypothesized that we would observe greater effects on
biomarkers in obese women and women with greater abdominal adiposity. For adiponectin,
women with a BMI ≥ 30 kg/m2 benefited most from a diet or diet+exercise intervention with
respect to adipokine concentrations. We hypothesized that changes in weight and body fat
would substantially modify the effects on adipokine concentrations. Changes in body
composition influenced leptin independent of the intervention group. The results stratified
by the proportion of weight and body fat loss showed strong trends from lesser to greater
weight loss or body fat loss in the diet and diet+exercise intervention groups. These results
are consistent with our hypothesis that greater reductions in weight, and specifically body
fat, are needed to affect adiponectin and leptin concentrations.
Our study has broad implications with respect to the risk of cancer and other metabolic
diseases. The most recent report from the World Cancer Research Fund stated that the link
between obesity and cancer is convincing for cancers of the breast in postmenopausal
women, colorectum, endometrium, kidney, pancreas, and esophagus [5]. Maintaining a
healthy body weight, increasing physical activity, and limiting energy-dense foods and
drinks are some of the recommendations to reduce the risk of cancer [5]. Adipose tissue
produces adiponectin and leptin, which are thought to mediate the effects of obesity on the
risk of cancer, partially by influencing inflammatory and immune responses [36].
A number of recent prospective studies have reported that adiponectin and leptin may play a
role in carcinogenesis, as follows: the Nurses’ Health Study reported an inverse association
between adiponectin concentrations and postmenopausal breast cancer risk [37]; a nested
case-control study involving 18,225 men showed that low serum adiponectin concentrations
are associated with a higher risk of colorectal cancer [38]; and data from a cohort in Norway
showed a nearly three-fold increased risk of colon cancer among people with high leptin
concentrations independent of BMI [39]. A systematic review of adiponectin and cancer
concluded that measurement of adiponectin might serve as a useful means for predicting risk
of obesity-related cancers [40]. Additionally, there is a defined relationship between insulin
sensitivity, fasting insulinemia and plasma adiponectin [41, 42]. A meta-analysis of 13
prospective studies showed an inverse link between the incidence of type 2 diabetes and
plasma adiponectin levels [43]. The risk of developing type 2 diabetes decreases with
increasing adiponectin concentrations, potentially due to suppression of hepatic
gluconeogenesis, stimulation of fatty acid oxidation, and glucose uptake in skeletal muscle
[43-45]. Furthermore, studies have shown that serum adiponectin may be used as a
biomarker predicting all-cause and cardiovascular mortality in patients with type 2 diabetes
[14]. To gain more detailed knowledge, additional research is needed in establishing
standardized routine adiponectin measurement methods and expertise in interpretation of the
results [15]. Associations between obesity and leptin with cardiovascular, endocrine, and
inflammatory processes have been described. Leptin is responsible for energy regulation and
satiety, thus leptin is strongly correlated with body fat [16]. A reduction in elevated leptin
concentrations in the circulation can lead to an improvement in blood lipid levels, blood
pressure, and insulin sensitivity [46, 47].
This current study is the first to examine the individual and combined effects of a 12-month
dietary and aerobic exercise intervention on circulating adiponectin and leptin
concentrations in a large sample of overweight and obese postmenopausal women. The

strengths of the study include the large study size, with sufficient power to assess long-term
changes in adiponectin and leptin concentrations, a randomized controlled design with three
intervention groups, high retention (91%), and high adherence to the intervention programs.
Another key strength of the study was that this approach can be instituted clinically or by
well-motivated individuals and groups; the group-based modification of the DPP
intervention can be easily adopted and the exercise component, which consisted primarily of
brisk walking, is similarly applicable [25].
We recognize that there are some limitations to the current study. The generalizability of
these results may be limited by the relatively homogeneous sample of postmenopausal
women. The study population was primarily non-Hispanic white women, and the effects of
weight loss or exercise on adipokines in women from other races or ethnic groups cannot be
inferred without additional data. Furthermore, only one dietary weight loss program and one
exercise program were tested; therefore, we are unable to speculate on the effects of other
weight loss methods or other types or intensities of exercise programs on adiponectin and
leptin levels. Our results and various available diet and exercise intervention programs need
to be studied, and in different ethnicities for potential implementation into clinical practice.
In conclusion, dietary weight loss intervention, with or without exercise, increased the serum
adiponectin concentration in overweight and obese postmenopausal women, whereas
exercise alone showed limited beneficial effects. Substantial weight loss or percent body fat
loss due to dietary weight loss interventions resulted in an increase in the adiponectin
concentration, and reduction in leptin of > 50%. The results from our study can provide
insight into the biologic mechanisms that mediate the effects of weight loss and exercise on
cancer risk, as well as providing further data on the public health impact of relatively simple
lifestyle interventions on diet and weight.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We would like to thank the study staff and the participants for their dedication to the study.
Financial Support:
This work was supported by the National Cancer Institute at the National Institutes of Health (grants U54-
CA116847, R01 CA102504; 5KL2RR025015-03 to K.F.S; R25 CA94880 and R25CA057699 to A.K.); and the
Canadian Institutes of Health Research (Fellowships to K.L.C & C.M). None of the funding agencies were involved
in the trial design or conduct. During the trial, Dr. Alfano was a faculty member at Ohio State University, and
relocated to the NCI following completion of her efforts on the NEW trial.
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Figure 1.
CONSORT diagram of the Nutrition and Exercise for Women (NEW) trial

Figure 2.
Effect of individual and combined dietry weight loss and excercise interventions on
adiponectin and leptin, startified by change in % body fat (geometric mean)

Table 1
Baseline characteristics of study participants (N=438)
Control Diet Diet+Exercise Exercise
(N=87) (N=118) (N=116) (N=117)
Age, mean (SD) 57.4 (4.4) 58.1 (5.9) 58.0 (4.4) 58.1 (5.0)
Ethnicity No. (%)

Non-Hispanic white 74 (85.1) 101 (85.6) 99 (85.3) 98 (83.8)
African American 6 (6.9) 9 (7.6) 15 (12.8) 5 (4.3)
Asian/Pacific Islander 2 (2.3) 2 (1.7) 2 (1.7) 2 (1.7)
Hispanic/Latino 3 (3.4) 2 (1.7) 2 (1.7) 5 (4.3)
Other 2 (2.3) 4 (3.4) 0 (0.0) 5 (4.3)
Education
College degree, No. (%) 59 (67.8) 76 (64.4) 81 (69.8) 70 (59.8)
Marital status
Married or have partner, No. (%) 59 (67.8) 79 (67.0) 69 (60.0) 71 (60.7)
Smoking
Ever smoked, No. (%) 32 (36.8) 55 (46.6) 47 (40.5) 47 (40.2)
Anthropometrics
BMI, mean (SD), kg/m2 30.7 (3.9) 31.0 (3.9) 31.0 (4.3) 30.7 (3.7)
Body fat, mean (SD), % 47.8 (4.5) 47.6 (4.4) 47.9 (4.6) 47.9 (4.1)
Body fat mass (kg) 40.1 (8.5) 39.8 (8.1) 39.9 (8.2) 39.4 (7.9)
Waist circumference, mean (SD), cm 94.8 (10.2) 94.6 (10.2) 93.7 (9.9) 95.1 (10.1)
Lifestyle behaviors
Aerobic fitness, mean (SD), mL/kg/min 23.1 (4.1) 22.6 (3.8) 23.6 (4.1) 22.5 (4.1)
Physical activity, mean (SD), min/week 23.8 (41.2) 33.6 (45.5) 32.4 (42.9) 37.7 (43.7)
Total calorie intake, mean (SD), kcal/day 1988 (669) 1884 (661) 1894 (639) 1986 (589)
Percent calorie intake from fat, mean

(SD), % 35.6 (6.9) 33.1 (6.3) 35.3 (7.3) 33.6 (6.9)

NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 2
Effect of individual and combined dietary weight loss and exercise interventions on adiponectin and leptin (geometric mean)
Baseline 12-Months Δ from Baseline

to 12-Months
N Mean (95% CI) N Mean (95% CI) Δ (%) Pvalue

Abbenhardt et al.
Adiponectin (μg/mL)
Diet+Exercise 116 12.8 (11.7, 13.9) 116 13.6 (12.5, 14.8) +0.8 (6.6) 0.0001
Diet 118 12.4 (11.3, 13.5) 118 13.5 (12.5, 14.6) + 1.2 (9.5) <0.0001
Exercise 117 12.5 (11.5, 13.5) 117 12.1 (11.1, 13.2) −0.3 (−2.6) 0.82
Control 87 12.8 (11.7, 14.0) 87 12.4 (11.3, 13.5) −0.4 (−3.3) Ref.
Leptin (ng/mL)
Diet+Exercise 116 23.8 (22.0, 25.6) 116 14.2 (12.8, 15.8) −9.5 (−40.1) <0.0001
Diet 118 23.1 (21.4, 24.9) 118 16.8 (15.2, 18.6) −6.3 (−27.1) <0.0001
Exercise 117 23.5 (21.7, 25.4) 117 20.5 (18.8, 22.4) −3.0 (−12.7) 0.005
Control 87 24.9 (22.9, 26.9) 87 24.4 (22.2, 26.8) −0.5 (−1.9) Ref.
GEE model, Last observation carried forward for 12-month missing values overall n=40 (8 control, 13 diet, 11 exercise, 8 diet+exercise), P<0.05/6=0.0083 considered statistically significant
Pvaiues comparing changes in adiponectin and leptin (adjusting for baseline values) vs. control

Page 15
Table 3
Effect of individual and combined dietary weight loss and exercise interventions on adiponectin and leptin, stratified by baseline BMI
(geometric mean)
Control Diet
Abbenhardt et al.
Baseline 12-month Baseline 12-month
N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P*
BMI<30 kg/m2 41 14.1 (12.5-15.9) 37 14.2 (12.6-16.0) +0.1 +0.9 55 12.8 (11.2-14.5) 53 14.6 (13.0-16.4) +1.8 +14.1 0.001
BMI>30 kg/m2 46 11.7 (10.4-13.2) 42 11.1 (9.7-12.6) −0.7 −5.6 63 12.0 (10.8-13.4) 52 12.4 (11.1-13.9) +0.4 +3.3 0.002
**P=0.59
Leptin (ng/mL)
BMI<30 kg/m2 41 19.8 (17.8-22.0) 37 19.4 (16.8-22.4) −0.4 −1.9 55 18.1 (16.5-20.0) 53 12.0 (10.5-13.6) −6.2 −34.1 <0.0001
BMI>30 kg/m2 46 30.4 (28.0-33.0) 42 30.4 (27.1-34.0) −0.1 −0.2 63 28.5 (26.2-30.9) 52 20.7 (18.4-23.4) −7.7 −27.1 <0.0001
**P=0.31
Exercise Diet+Exercise
N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P
BMI<30 kg/m2 57 13.6 (11.9-15.5) 53 13.3 (11.6-15.3) −0.3 −1.9 0.99 56 14.8 (13.4-16.3) 53 15.9 (14.5-17.5) 1.1 +7.7 0.046

BMI>30 kg/m2 60 11.5 (10.4-12.7) 53 11.0 (9.8-12.3) −0.5 −4.5 0.85 60 11.1 (9.8-12.6) 55 12.3 (10.8-13.9) 1.1 +10.2 <0.0001
p-inter=0.85 **P=0.68
Leptin (ng/mL)
BMI<30 kg/m2 57 18.6 (16.8-20.6) 53 16.2 (14.3-18.3) −2.4 −3.0 0.09 56 18.8 (17.0-20.7) 53 10.2 (8.9-11.7) −8.6 −45.6 <0.0001
BMI>30 kg/m2 60 29.4 (26.9-32.0) 53 25.6 (23.0-28.5) −3.8 −2.9 0.02 60 29.6 (27.2-32.2) 55 18.4 (16.3-20.8) −11.2 −37.8 <0.0001
p-inter=0.89 **P=0.28
LL: lower limit of 95% confidence interval; UL: Upper limit of 95% confidence interval.
*
Pvalue comparing change from baseline to 12-months follow-up in intervention group versus controls within BMI strata.
Page 16
**
Pvalue comparing difference in change from baseline to 12-months in intervention group versus controls in high BMI strata versus low BMI strata.
Abbenhardt et al.

Page 17
Table 4
Effect of individual and combined dietary weight loss and exercise interventions on adiponectin and leptin, stratified by percent weight loss
(geometric mean)
Control Diet
Abbenhardt et al.
N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P*
Adiponectin
(Mg/mL)
Weight loss <5% 67 12.9 (11.6-14.2) 66 12.2 (11.1-13.5) −0.6 −4.9 28 10.8 (9.4-12.5) 28 10.7 (9.4-12.3) −0.1 −0.8 0.18
Weight loss 5-10% 9 13.7 (10.3-18.2) 9 15.3 (11.4-20.5) +1.6 +11.3 27 13.4 (11.3-15.9) 27 14.9 (12.8-17.4) +1.5 +11.0 0.96
Weight loss ≥10% 4 10.7 (7.6-15.2) 4 10.3 (7.8-13.6) −0.4 −3.7 49 12.1 (10.5-13.9) 49 14.3 (12.7-16.1) +2.2 +18.5 0.02
‡ ‡‡
P =0.62; P =0.02
P-trend=0.0002
Leptin (ng/mL)
Weight loss <5% 67 25.0 (22.8-27.4) 66 25.8 (23.2-28.7) +0.8 +3.3 28 24.0 (21.2-27.1) 28 24.1 (21.5-27.1) +0.1 +0.6 0.64
Weight loss 5-10% 9 22.8 (16.9-30.8) 9 19.5 (15.1-25.3) −3.3 −14.6 27 22.6 (19.9-25.7) 27 17.1 (14.7-19.9) −5.5 −24.3 0.12
Weight loss ≥10% 4 32.3 (25.6-40.7) 4 19.6 (8.7-44.5) −12.7 −39.3 49 21.9 (19.2-24.9) 49 11.9 (10.2-13.7) −10.0 −45.8 0.67
‡ ‡‡
P =0.29;P =0.60
P-trend=<0.0001

Adiponectin
(μg/mL)
Weight loss <5% 75 12.7 (11.4-14.2) 75 12.2 (10.8-13.7) −0.6 −4.5 .80 18 11.9 (10.3-13.8) 18 11.5 (9.9-13.5) −0.4 −3.4 0.59
Weight loss 5-10% 26 11.3 (9.6-13.3) 26 11.6 (9.8-13.7) +0.2 +2.2 .14 21 11.0 (8.7-13.9) 21 11.2 (8.9-14.1) +0.2 +2.1 0.12
Weight loss ≥10% 4 13.4 (12.0-15.1) 4 12.8 (10.2-15.9) −0.7 −4.9 .94 69 14.0 (12.7-15.5) 69 15.6 (14.3-17.1) +1.6 +11.7 0.07
‡ ‡‡ ‡ ‡‡
P =0 10;P =0.98 P =0.07;P =0.047
Page 18
P-trend=0.0005
Abbenhardt et al.
Leptin (ng/mL)
Weight loss <5% 75 23.1 (21.0-25.5) 75 21.9 (19.8-24.2) −1.3 −5.4 .047 18 27.4 (23.0-32.5) 18 28.0 (23.9-32.8) +0.6 +2.2 0.93
Weight loss 5-10% 26 24.6 (20.6-29.5) 26 17.5 (14.4-21.3) −7.1 - .045 21 21.4 (17.9-25.7) 21 15.0 (11.9-19.0) −6.4 −29.9 0.01
Weight loss ≥10% 4 21.7 (12.4-37.9) 4 11.0 (6.3-19.1) −10.7 - .56 69 23.9 (21.6-26.4) 69 11.2 (10.0-12.4) −12.7 −53.2 0.33
‡ ‡‡ ‡ ‡‡
P =0.43;P =0.63 P =0.03;P =0.26
P-trend=<0.0001
LL: lower limit of 95% confidence interval; UL: Upper limit of 95% confidence interval.
*
Pvalue comparing change from baseline to 12-months follow-up in intervention group versus controls within weight-loss strata.
**
Pvalue comparing difference in change from baseline to 12 months in intervention group versus controls in high weight-loss strata versus low weight-loss strata.
‡
Pvalue comparing difference in change from baseline to 12 months in intervention group versus controls in middle weight-loss strata versus low weight-loss strata.
‡‡
Pvalue comparing difference in change from baseline to 12 months in intervention group versus controls in high weight-loss strata versus low weight-loss strata.

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J Intern Med. 2013 August ; 274(2): 163–175. doi:10.1111/joim.12062.

Effects of individual and combined dietary weight loss and

Methods—Overweight/obese postmenopausal women (n=439) were randomized as follows: 1) a

J Intern Med. Author manuscript; available in PMC 2014 August 01.

Subjects and Methods

We used permuted-block randomization (ratio 0.75:1:1:1) to assign a proportionally smaller

Interventions and Control Group

J Intern Med. Author manuscript; available in PMC 2014 August 01.

The exercise intervention goal was 45 minutes of moderate-to-vigorous intensity exercise 5

Adiponectin was measured by a commercially available radioimmunoassay (Millipore Inc.,

inter-assay coefficients of variation (CV) were 8.4% and 9.8%, respectively.

Leptin assays were performed with a commercially available radioimmunoassay (Millipore

We assessed demographics, medication use, lifestyle behaviors, and anthropometrics at

J Intern Med. Author manuscript; available in PMC 2014 August 01.

J Intern Med. Author manuscript; available in PMC 2014 August 01.

An evaluation of the effects of the interventions on adipokines stratified by BMI is presented

J Intern Med. Author manuscript; available in PMC 2014 August 01.

J Intern Med. Author manuscript; available in PMC 2014 August 01.

J Intern Med. Author manuscript; available in PMC 2014 August 01.

2:323–5. [PubMed: 11225749]

J Intern Med. Author manuscript; available in PMC 2014 August 01.

reviews. 2011; 69:599–612. [PubMed: 21967160]

J Intern Med. Author manuscript; available in PMC 2014 August 01.

physiology: emerging clinical applications. Annals of internal medicine. 2010; 152:93–100.

J Intern Med. Author manuscript; available in PMC 2014 August 01.

J Intern Med. Author manuscript; available in PMC 2014 August 01.

J Intern Med. Author manuscript; available in PMC 2014 August 01.

Control Diet Diet+Exercise Exercise

(N=87) (N=118) (N=116) (N=117)

Ethnicity No. (%)

African American 6 (6.9) 9 (7.6) 15 (12.8) 5 (4.3)

Asian/Pacific Islander 2 (2.3) 2 (1.7) 2 (1.7) 2 (1.7)

Hispanic/Latino 3 (3.4) 2 (1.7) 2 (1.7) 5 (4.3)

Other 2 (2.3) 4 (3.4) 0 (0.0) 5 (4.3)

Ever smoked, No. (%) 32 (36.8) 55 (46.6) 47 (40.5) 47 (40.2)

Percent calorie intake from fat, mean

J Intern Med. Author manuscript; available in PMC 2014 August 01.

Baseline 12-Months Δ from Baseline

N Mean (95% CI) N Mean (95% CI) Δ (%) Pvalue

J Intern Med. Author manuscript; available in PMC 2014 August 01.

Baseline 12-month Baseline 12-month

N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P*

Baseline 12-month Baseline 12-month

N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P

J Intern Med. Author manuscript; available in PMC 2014 August 01.

J Intern Med. Author manuscript; available in PMC 2014 August 01.

Baseline 12-month Baseline 12-month

N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P*

J Intern Med. Author manuscript; available in PMC 2014 August 01.

N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P

Baseline 12-month Baseline 12-month

N Mean (LL-UL) N Mean (LL-UL) Δ % P N Mean (LL-UL) N Mean (LL-UL) Δ % P

J Intern Med. Author manuscript; available in PMC 2014 August 01.

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