Exercise and the metabolic syndrome with weight

regain

Tom R. Thomas, Shana O. Warner, Kevin C. Dellsperger, Pamela S. Hinton,

Adam T. Whaley-Connell, R. Scott Rector, Ying Liu, Melissa A. Linden, Anand
Chockalingam, John P. Thyfault, David R. Huyette, Ze Wang and Richard H. Cox
J Appl Physiol 109:3-10, 2010. First published 18 February 2010; doi:10.1152/japplphysiol.01361.2009
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J Appl Physiol 109: 310, 2010.

First published February 18, 2010; doi:10.1152/japplphysiol.01361.2009.

Exercise and the metabolic syndrome with weight regain

Tom R. Thomas,1 Shana O. Warner,1 Kevin C. Dellsperger,2,3 Pamela S. Hinton,1
Adam T. Whaley-Connell,2,4 R. Scott Rector,1,2 Ying Liu,1 Melissa A. Linden,1 Anand Chockalingam,2,4
John P. Thyfault,1,2,4 David R. Huyette,2 Ze Wang,5 and Richard H. Cox5
1

Department of Nutrition and Exercise Physiology, 2Department of Internal Medicine, 3Department of Medical Pharmacology
and Physiology, 4Harry S. Truman Veterans Affairs Medical Center, and 5Department of Educational, School,
and Counseling Psychology, University of Missouri, Columbia, Missouri

Submitted 7 December 2009; accepted in final form 11 February 2010

lifestyle intervention; abdominal fat; glucose homeostasis; lipoproteins

AMERICANS are experiencing an obesity epidemic, with US
adults and children gaining weight at unprecedented rates, and
the increased prevalence of lifestyle-related diseases such as
Type 2 diabetes and cardiovascular disease (CVD) is accompanying this weight trend (9). Although obesity itself is a risk
factor for chronic diseases, most of the increased risk of
disease may be associated with the clustering of risk factors
termed the metabolic syndrome (MetS). Epidemiological studies suggest increased prevalence of morbidity and mortality in
individuals with the MetS (17), and estimates of the national

Address for reprint requests and other correspondence: T. R. Thomas,

113 McKee Gym, Univ. of Missouri, Columbia, MO 65211 (e-mail:
thomastr@missouri.edu).
http://www.jap.org

medical expenditures attributed to the MetS have surpassed

$80 million (28).
Weight loss, whether by energy restriction, increased energy
expenditure, or a combination of the two strategies, is an effective
way of improving metabolic health, as indicated by beneficial
changes in insulin sensitivity (15), abdominal adiposity (11, 15),
blood lipid profile (35), markers of inflammation (7), and blood
pressure (5). The benefits of weight loss are clear in the scientific
literature; what is less clear is the impact of exercise during cycles
of weight loss and regain, which are common in overweight
individuals (21). Recent data suggest that weight often is regained
in a short period of time (14, 26, 31, 32), and even chronic
exercisers may gain weight over time (34).
Results from numerous studies indicated that weight loss is
not necessary to achieve the beneficial effects of exercise
training on chronic disease risk parameters of insulin sensitivity (3), abdominal obesity (29), lipoprotein profile (27), C-reactive protein (CRP) (20), and blood pressure (5). Given that
exercise is effective with or without weight loss, it follows that
exercise may be beneficial even during periods of weight
regain. In support of this concept, epidemiological studies
suggest that fitness dramatically reduces the risk of death in
overweight men (2, 22), and physical activity reduces the risk
of adverse events in overweight women with coronary heart
disease (CHD) (33). Collectively, these results suggest that
exercise training may improve risk status regardless of weight.
Improved health profile in the face of weight gain has
important implications to national health policies. In high-risk
adults, the retention of beneficial metabolic effects may play an
important role in preventing disease symptoms and events.
Using a novel model of controlled weight regain in humans,
the purpose of this study was to determine if aerobic exercise
training effectively maintains improvements to MetS variables
during partial weight regain. We hypothesized that exercise
training would prevent deterioration of metabolic parameters
during controlled weight regain.
METHODS

Study Participants
The primary criteria for participation were overweight to Class II
obese [body mass index (BMI) 2539.9 kg/m2] and sedentary, i.e., no
more than one systematic exercise session over 30-min duration per
week over the previous 4 mo. Subjects were weight stable for the
previous 3 mo, as determined by questionnaire. All subjects had at
least two characteristics and 60% had three to five characteristics of
the MetS as defined by the third report of the National Cholesterol
Education Program (8). Subject characteristics and incidence for
individual MetS variables are presented in Table 1. There were no
significant differences between groups on any baseline characteristic.
3

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Thomas TR, Warner SO, Dellsperger KC, Hinton PS, WhaleyConnell AT, Rector RS, Liu Y, Linden MA, Chockalingam A, Thyfault
JP, Huyette DR, Wang Z, Cox RH. Exercise and the metabolic syndrome
with weight regain. J Appl Physiol 109: 310, 2010. First published February
18, 2010; doi:10.1152/japplphysiol.01361.2009.Weight loss improves
metabolic syndrome (MetS) factors, but risk may return with weight
regain. This study was designed to determine if exercise training can
maintain improvements in MetS risk factors during weight regain. In
a randomized control trial,102 overweight or obese (body mass index
25.0 39.9 kg/m2) men and women (age 2152 yr), with characteristics of the MetS, lost 10% of body weight with supervised walking/
O2max) (400
jogging at 60% of maximal oxygen consumption (V
kcal/session), 5 days/wk, and caloric restriction (600 kcal/day) over
a 4- to 6-mo period. After weight loss, 77 remaining subjects underwent programmed weight regain (50% of lost weight) for 4 6 mo
with random assignment to two groups: no exercise (NoEX) or
continued supervised exercise (EX). Blood pressure, regional fat,
glucose homeostasis, lipids, and inflammatory markers were assessed
at baseline, post-weight loss, and post-weight regain. Groups were
compared by two-way repeated-measures ANOVA on the 67 subjects.
After weight loss (9.7 0.2% of body weight), significant (P 0.05)
improvements were observed in almost all parameters assessed. Following weight regain (54.4 1.6% of lost weight), the NoEX group
exhibited deterioration in most metabolic markers, while the EX
O2max, blood pressures, glucose
group maintained improvements in V
homeostasis, high- and low-density lipoprotein cholesterol (HDL-C
and LDL-C), oxidized LDL, and other markers of inflammation, but
did not maintain improvements in triglyceride and cholesterol concentrations or abdominal fat. Results of this design of controlled
human weight regain suggest that aerobic exercise can counter the
detrimental effects of partial weight regain on many markers of
disease risk.

EXERCISE AND WEIGHT REGAIN

Table 1. Subject characteristics and incidence of metabolic syndrome

Baseline

Variable
Age, yr
Weight, kg
BMI, kg/m2
Body fat, %
Waist-to-hip ratio
O2max, l/min
V
O2max, ml kg1 min1
V
Resting HR, beats/min
Metabolic syndrome variables
Waista, cm
BP systolicb, mmHg
BP diastolicb, mmHg
Glucosec, mg/dl
TGd, mg/dl
HDL-Ce, mg/dl

PWR

NoEX

EX

NoEX

EX

96.9*
34.4

97.1
17.1

90.6
31.3

97.1
8.6

18.8
40.6
56.3

25.7
40.0
48.6

21.9
31.3
37.5

25.7
28.6
25.7

40 1
96.15 1.91
32.8 0.5
34.8 0.8
0.94 0.01
2.64 0.09
27.5 0.6
75 1
% Incidence

109.3 1.2
122 1
79 1
94.4 1.1
155.0 11.5
45.9 1.5

Exclusion criteria included diagnosed cardiovascular disease or

diabetes or disease symptom according to the American College of
Sports Medicine (1), smoking, menopause, or medications or supplements (e.g., fibrates, statins, metformin, thiazolidenediones, antihypertensives, fish oil) that could affect weight loss or variables of the
MetS. One-hundred two subjects (37 men, 65 women) started the
study, and 67 subjects (27 men and 40 women) completed both
phases. All participants provided written informed consent as approved by the Health Sciences Institutional Review Board at the
University of Missouri. The study was registered in ClinicalTrials.
gov [identifier: NCT00543985 (http://www.clinicaltrials.gov/ct2/show/
NCT00543985?termmetabolicsyndrome&state1NA%3AUS%
3AMO&rank6)].
Interventions
Weight loss treatment protocols. All subjects were assigned individual exercise and diet programs designed to induce a loss of
10% body weight titrated over a 4- to 6-mo period (Fig. 1), which
for most participants was a rate of loss of 0.2 0.4 kg/wk. The
average daily energy deficit required for an individual to achieve
this amount of weight loss over the 6-mo period was estimated
from the initial body weight and an energy deficit of 7,700 kcal for

PWL

Fig. 1. Design of the study. NoEX, no exercise training; EX, exercise training;
PWL, post-weight loss; PWR, post-weight regain.
J Appl Physiol VOL

1 kg of weight loss. A combination of increased energy expenditure and decreased energy intake was used to achieve the target
daily energy deficit.
The exercise program for weight loss consisted of supervised
walking or jogging exercise in a fitness center within the Exercise
Physiology Lab complex at the University of Missouri. To prevent
lower extremity injury or discomfort in this previously sedentary
population, a ramping protocol was used to attain the desired level of
training. Week 1 consisted of treadmill exercise at 50% of aerobic
O2max) or 75% of maximal heart rate (HRmax) for 20
capacity (V
min/day, 5 days/wk. Weeks 2 and 3 consisted of treadmill exercise at
O2max for 30 and 45 min/day, respectively, 5 days/wk. By
50% of V
week 4, subjects were training at the desired intensity of 60% of
O2max for 45 min/day, 5 days/wk (200 min/wk, 2,000 2,500
V
kcal/wk) (4), where they remained for the duration of the study. The
exercise intensity was monitored daily by the personal trainer assigned to the subject. In addition, stationary cycling and elliptical
exercise were used for recovery/rehabilitation when muscle or joint
injuries occurred. This quantity of exercise paralleled that recommended by the Institute of Medicine (4). The weight loss was
monitored one to two times weekly, and adjustments to the exercise
and diet prescription were made as necessary. The average kilocalorie
O2) and
deficit targets were 450 kcal/day for exercise (measured V
600 kcal/day for diet.
At the beginning of the study, a nutritionist met with the subjects
to discuss overall dietary health (e.g., food pyramid, importance of
fruits and vegetables, dairy, etc.), present simple strategies to reduce
energy intake, and teach subjects how to read and interpret food
labels. The nutritionist met with each subject to evaluate habitual diet
and develop an individualized plan to reduce energy intake. Subjects
kept a daily food intake record throughout the study, and a study
nutritionist utilized the records each week to provide each participant
with specific suggestions on how to modify the diet to achieve the
prescribed energy deficit. Total energy and macronutrient composition
of the diet were estimated at baseline, post-weight loss (PWL), and
post-weight regain (PWR) from the written daily food records using
the Food Processor software, version SQL (ESHA, Salem, OR).
Weight regain treatment protocols. The second phase of the study
was 4- to 6-mo duration and was the primary focus of the research.
After completing the weight loss phase of the study, subjects were
randomly assigned to two groups: partial weight regain with no
exercise training (NoEX) or partial weight regain with exercise

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O2max, maximal oxygen

Values are means SE. BMI, body mass index; PWR, post-weight regain; EX, exercise training; NoEX, no exercise training; V
consumption; HR, heart rate. *Percentage of subjects within group. aWaist circumference: men, 102 cm, women, 88 cm. bBlood pressure (BP) 130/85
mmHg. cFasting blood glucose 100-125 mg/dl. dFasting triglycerides (TG) 150 mg/dl. eHigh-density lipoprotein-cholesterol (HDL-C): men, 40 mg/dl,
women, 50 mg/dl.

EXERCISE AND WEIGHT REGAIN

J Appl Physiol VOL

A given female subject had blood collected at the same phase of the
menstrual cycle (follicular or luteal) during each testing period.
Glucose, triglyceride (TG), and cholesterol concentrations were
measured with colorimetric kits (Thermo, Arlington, TX). Plasma
high-density lipoprotein (HDL)-cholesterol (C) and subfractions, less
dense HDL2 and denser HDL3, were determined using a modified
heparin-MnCl2-dextran sulfate method (6), and low-density lipoprotein (LDL)-C was calculated according to the Friedewald equation
(10). Insulin and C-reactive protein (CRP) were measured with an
immunoassay system (Immulite 1000, Siemens, New York). Oxidized
LDL (oxLDL) concentration was analyzed with a commercially
available enzyme-linked immunosorbent assay (ELISA) (Mercodia,
Uppsala, Sweden). TNF- and its soluble receptor two (TNFRII) were
assessed using ELISA kits (R&D Systems, Minneapolis, MN). Homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index (QUICKI) were calculated and used as estimates of
insulin resistance and sensitivity, respectively. Coefficient of variation
averaged 2.0% and was less than 4.5% for all analyses.
Statistical analysis. A priori power analyses were conducted to
calculate the samples sizes needed to detect the effect sizes of
interventions at PWL vs. PWR. All participants were treated as one
group in the weight loss phase and treated as two groups in the weight
regain phase (Fig. 1). We calculated that an n of 34 participants per
group would detect a medium effect of d 0.50 at power 0.80,
0.05.
Values are presented as means and SE, and level was set at 0.05
for all comparisons. To verify changes in the metabolic parameters
with weight loss, data from the phase 1 weight loss, the single group
was analyzed using a one-factor (time) ANOVA with repeated measures (baseline vs. PWL) (Fig. 1). For phase 2 weight regain, data
were analyzed using a group (NoEX and EX) by time (baseline, PWL,
and PWR) ANOVA with repeated measures on time. Bonferroni
adjustment was applied when there were multiple comparisons for a
variable.
RESULTS

Of the 102 subjects who began the study, 67 subjects, ages

2152 yr, completed both phases of the study and were included in the statistical analysis and are characterized in Table
1. The dropout rate at the end of weight loss was 27% and after
both phases was 31%. Subjects completed 96% of all assigned
exercise sessions during both phases (%compliance no. of
sessions attended/total no. of sessions required 100). The
average exercise performance during the study was 4.8 sessions/wk and 2,000 kcal/wk. The incidence of MetS characteristics at baseline and PWR is listed in Table 1.
Dietary analysis of each time point is summarized in Table 2.
Although groups were not formed at baseline, the group means
are presented to assess retrospectively changes between baseline and PWR. Dietary intake of each macronutrient was
reduced during the weight loss phase and then tended to go
back toward baseline values during the regain period. Carbohydrate and calcium in the EX group and energy, carbohydrate,
and fiber in the NoEX group were significantly different
between baseline and PWR.
As prescribed, subjects lost 9.7% of body weight during the
weight loss phase and gained back 54.4% of the lost weight in
the regain phase (Fig. 2). BMI paralleled body weight changes
(Fig. 2) as did percent fat, in which the total group exhibited a
significant loss of 3% fat during weight loss and each group a
O2max was
significant increase of 1.3% fat during regain. V
significantly increased by 11% during the weight loss period
and then was maintained during the regain period in the EX
group but decreased significantly by 7% during regain in the

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training (EX) (Fig. 1). For randomization, subjects were divided into
pairs based on sex and the time scheduled to finish the weight loss
phase. The first participant in the pair to complete the weight loss
phase was assigned to either the EX or NoEX group based on a coin
flip, and the second participant of that pair was then assigned to the
other group.
Subjects who were randomized to the NoEX group discontinued
exercise training and were provided an energy intake prescription
designed to cause regain of 50% of the lost body weight over 4 6 mo,
with focus on the addition of healthy dietary energy. In addition, each
subject in the NoEX group was required to report to the lab a
minimum of 12 days/wk for weigh-in, diet diary analysis, and
counseling. Utilizing the daily food records, modifications to the diet
prescriptions were made as needed.
O2max, as
Subjects in the EX group continued to exercise at 60% V
reassessed by a second maximal stress test for 5 days/wk as in the
weight loss phase. During the regain phase, at least three exercise
sessions per week were performed under supervision in the fitness
center. The 12 days/wk unsupervised sessions were monitored using
pedometers, heart rate (HR) monitors, and activity logs. Others have
shown that unsupervised exercise sessions can be monitored accurately using pedometers or accelerometers (13, 30).
Thus, in the EX group, the target positive energy balance was
achieved only by increasing energy intake. The dietary energy intake
was increased from the weight loss phase based on the new body
weight and the exercise kilocalorie deficit. The dietary intake was
adjusted weekly by the study nutritionist or assistant as necessary with
the goal to regain steadily over the 4- to 6-mo period. Healthy snacks
(e.g., protein bars, dried fruits, and nuts) were provided during the
regain period to help participants meet energy intake goals.
Outcome variables. Measurements on outcome variables were
performed at baseline, PWL, and PWR. For a given subject, a single
technician made all measurements at the three time points. Weight
was measured using a Toledo scale sensitive to 100 g and height
measured using a wall tape calibrated to 0.1 cm. Waist circumference
was measured to the nearest 0.1 cm with a spring-loaded metal tape.
Body composition was estimated using QDR-4500A dual X-ray
absorptiometry (Hologic, Shelby Township, MI).
After the subject sat quietly in a padded chair for 15 min, systolic
(SBP) and diastolic blood pressures (DBP) were measured using a
standard aneroid sphygmomanometer. Each subject underwent a cardiologist-supervised treadmill stress test to volitional exhaustion using
O2max using a True One 2400 (Parvo,
the Bruce protocol to assess V
Sandy, UT) metabolic cart.
Computed tomography (CT) on a Siemens Somatom Sensation 4
(Forchheim, Germany) was used for determination of cross-sectional
abdominal adipose tissue at the level of the L4 L5 vertebral disc
space as described by Kelley et al. (12, 16). Using a blinded, single
technician strategy, total abdominal adipose tissue (TAT) was divided
into visceral (VAT) and total subcutaneous (TSAT) by manual tracing
along the borders of the abdominal wall musculature. TSAT was
further subdivided into superficial (SSAT) and deep (DSAT) compartments by a manual tracing along the subcutaneous fascia.
To standardize food intake before each testing session for measuring blood parameters, each subject used a self-selected 48-h diet with
12-h fast before baseline blood collection and then repeated this
personalized 48 h diet before each blood sampling day. An attempt
was made to have all subjects weight stable for 2 wk before and
during the posttesting periods.
Following a 48-h dietary control with 12-h fast, blood samples
were collected, separated in a refrigerated centrifuge for plasma and
serum, and stored at 80C until analyzed. All samples (baseline,
PWL, PWR) from a given subject were analyzed in a single run. We
previously observed that plasma volume corrections were not necessary due to the similar timing in association with exercise (48 h
post-training session) for each testing time period (unpublished data).

EXERCISE AND WEIGHT REGAIN

Table 2. Summary of key dietary markers

Baseline

PWL

PWR

Variables

EX (n 35)

NoEX (n 31)

EX (n 35)

NoEX (n 31)

EX (n 35)

NoEX (n 31)

Energy, kcal
Fat, g
CHO, g
Protein, g
Cholesterol, mg
Sat. fat, g
Trans fat, g
Calcium, mg
Fiber, g
Iron, mg
Vitamin C, mg
Vitamin D, g
Vitamin E, mg

2,279 83
98 6
269 12
88 3
294 19
30.7 1.6
1.5 0.2
839 58
17.9 1.0
15.3 0.7
64.6 6.7
1.63 0.25
4.9 0.6

2,348 89
104 6
283 12
88 4
289 20
31.1 1.7
2.0 0.2
835 62
18.1 1.0
15.3 0.8
59.9 7.2
1.68 0.27
4.5 0.6

1,734 68*
70 5*
212 10*
75 3*
247 16*
20.7 1.3*
0.8 0.2*
681 40*
17.9 1.2
12.7 0.7*
94.5 23.3
1.27 0.24
3.8 0.6

1,568 72*
66 5*
192 10*
71 3*
236 17*
19.5 1.3*
0.9 0.2*
684 42*
16.3 1.3
12.4 0.7*
71.8 24.7
1.40 0.26
4.4 0.6

2,429 128
103 7
307 17*
95 4
306 20
31.5 1.9
1.9 0.3
1,036 95*
19.9 1.0
16.5 1.0
69.3 9.2
1.72 0.32
5.0 0.4

2,050 136*
91 7
241 18*
84 5
259 22
26.8 2.0
1.5 0.3
767 101
15.4 1.1*
14.1 1.0
55.7 9.8
2.10 0.34
3.0 0.5

Values are means SE. CHO, carbohydrate. *Significantly different from Baseline. Significantly different from post-weight loss (PWL). Significantly
different, Ex vs. No EX. Note: although groups were not formed at baseline, the group means are presented in order to assess retrospectively changes between
baseline and PWR.

LDL-C was maintained in the EX group but not in the NoEX

group after regain (Fig. 4).
Waist circumference and abdominal adipose tissue compartments were significantly reduced with weight loss and then
increased significantly in both groups with weight regain
(Fig. 5). However, the PWR mean remained lower than baseline in both groups for all variables. SSAT and DSAT (data not
shown) results each paralleled those of TSAT.
OxLDL concentrations were decreased following weight
loss, and the reduction was maintained during weight regain in
the EX group (Fig. 6). Inflammatory marker changes were
small, but TNFRII was significantly reduced with weight loss,
and CRP and TNF- concentrations were significantly lower
than baseline after regain in the EX group only (Fig. 6). The
CRP result may have been due in part to the nonsignificantly

Fig. 2. Body weight, body mass index (BMI),

O2max), and
maximal oxygen consumption (V
blood pressure (BP). Data points are means SE.
*Significantly different, PWL vs. baseline. aSignificantly different, PWR vs. baseline within
group. bSignificantly different, PWL vs. PWR
within group. cSignificantly different, EX vs.
NoEX.

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NoEX group (Fig. 2). In addition, significant reductions in

DBP and SBP were maintained in the EX group, while the
NoEX group exhibited a significant increase in SBP during
weight regain (Fig. 2).
All measured markers of glucose homeostasis were significantly improved during weight loss. Insulin, HOMA, and
QUICKI were maintained in the EX group during regain but
not in the NoEX group (Fig. 3). All lipids and lipoproteins
were significantly improved after weight loss although
HDL-C was a trend only (Fig. 4). Cholesterol and TG
concentrations generally deteriorated following the regain
phase in both groups. HDL-C continued to increase and was
significantly different from baseline in both groups during
regain. HDL2-C also remained significantly higher than
baseline in both groups during regain (data not shown).

EXERCISE AND WEIGHT REGAIN

Fig. 3. Glucose homeostasis. Data points are

means SE. HOMA, homeostasis model assessment; QUICKI, quantitative insulin sensitivity check. *Significantly different, PWL vs.
baseline. aSignificantly different, PWR vs. baseline within group. bSignificantly different, PWL
vs. PWR within group. cSignificantly different,
EX vs. NoEX.

DISCUSSION

The results of the weight loss phase confirm the positive

impact of exercise training and weight loss on the MetS
variables and extend our understanding of the comprehensiveness of these effects. The primary hypothesis tested was that
the two groups would respond differently to the weight regain.
Using a novel controlled weight regain model, these results

show for the first time in humans that exercise can maintain
most aspects of metabolic health during partial weight regain.
O2max, resting DBP
The EX group exhibited maintenance of V
and SBP, glucose homeostasis, LDL-C, HDL-C, and oxLDL.
The results for insulin sensitivity (QUICKI) and resistance
(HOMA) (Fig. 3) follow other data, which indicated that acute
or chronic exercise has a marked impact on glucose homeostasis regardless of weight loss (3). Our results extend this finding
and further suggest that exercise has a beneficial impact on
insulin sensitivity and other metabolic parameters even in the

Fig. 4. Lipids and lipoproteins. Data points are

means SE. HDL-C, high-density lipoprotein
cholesterol; LDL-C, low-density lipoprotein cholesterol. *Significantly different, PWL vs. baseline. aSignificantly different, PWR vs. baseline
within group. bSignificantly different, PWL vs.
PWR within group.

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higher baseline value in the EX group (0.62 0.12) vs. the

NoEX group (0.39 0.12).

EXERCISE AND WEIGHT REGAIN

Fig. 5. Abdominal fat. Data points are means

SE. TATabd, total abdominal adipose tissue;
TSAT, total subcutaneous adipose tissue; VAT,
visceral adipose tissue. *Significantly different,
PWL vs. baseline. aSignificantly different, PWR
vs. baseline within group. bSignificantly different, PWL vs. PWR within group.

tein profile induced by exercise training with weight loss (35)

or without (27), maintenance of HDL-C, LDL-C, and oxLDL
during weight regain is a novel finding and suggests a powerful
impact of exercise on these important CVD risk factors despite
weight regain. Others have reported negative effects on lipoproteins during follow up to a weight loss program, presumably caused by the weight regain (18). The reason for the
significant increase in HDL-C in the NoEX group during
regain is unclear. This result could indicate a delayed response
to the exercise accumulated during the weight loss period.
Slentz et al. (27) reported on the stability of HDL-C for 14 days

Fig. 6. Inflammation markers. Data points are

means SE. OxLDL, oxidized low-density lipoprotein; CRP, C-reactive protein; TNFRII, tumor necrosis factor receptor II. *Significantly
different, PWL vs. baseline. aSignificantly different, PWR vs. baseline within group. bSignificantly different, PWL vs. PWR within group.

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face of weight gain. Although HOMA and QUICKI have

limitations as markers of glucose homeostasis, intravenous
glucose tolerance tests performed on a cohort of subjects in this
study confirmed the results of the QUICKI analysis (24). The
ability of exercise to maintain the improvements in these
metabolic variables despite the weight regain highlights the
potential of this treatment strategy in the prevention of Type 2
diabetes and associated health care costs.
Lipid and lipoprotein parameters were beneficially affected
by the weight loss, but the impact of the regain on lipids was
variable (Fig. 4). While others have reported improved lipopro-

EXERCISE AND WEIGHT REGAIN

J Appl Physiol VOL

different from each other on any other parameter at the end of the
regain period. It could be argued that to be more confident of the
exercise impact, the two groups should be significantly different at
the end of regain period on most variables. This was not the case.
Thus the interpretation of a positive impact of exercise is based on
less definitive comparisons between the PWL and PWR time
points within each group. On the other hand, the EX group
exhibited lower incidence of achieving threshold on three of the
five MetS variables than the NoEX group following regain (Table
1). When only those subjects with 3 MetS variables at baseline
were analyzed, results were similar to those for all subjects; that is,
only HOMA was significantly different between groups after
regain. The data indicate that the groups were separating on most
variables during the regain period, and an extended time period
(e.g., 1 yr) may produce more conclusive results. It is also possible
that a different exercise regimen may better counter the effects of
weight regain than the moderate aerobic prescription. For example, a higher intensity exercise with shorter duration could be used
or a different mode such as resistance training. However, it may
be difficult for overweight subjects to tolerate higher intensity
exercise.
Prescribing weight regain in human research carries an
ethical dilemma. Support for this approach can be rationalized
given the overwhelming number of individuals who regain
weight and thus the potential importance of the findings gained
from this design. Dietary markers suggested that the healthiness of the participants diets was not compromised during
regain vs. baseline, as only the reduction in fiber in the in
NoEX might be considered detrimental. This lack of overshoot
in the regain diet is noteworthy considering that the EX group
had to compensate with extra energy from diet for the increased energy expenditure during exercise (Table 2). On the
other hand, the carefully controlled diet during the regain
period may have partially accounted for the protection provided by exercise. However, the deterioration of the metabolic
variables in the NoEx group, who also were using healthy
overeating to gain weight, suggests that diet was not a part of
the protection during the regain period. In addition, in the
regain diet only CHO and calcium were different during regain
vs. baseline and the energy intake was similar baseline vs.
regain in the EX group, suggesting that exercise at least has the
ability to protect if a person returns to the pre-weight loss diet.
However, the study design does not allow conclusions on
whether exercise could counter a less healthy or more excessive diet during a regain period.
Most individuals who participate in exercise and diet programs are successful at losing weight. However, it is also
common for many of these individuals to relapse and regain the
weight. To our knowledge this is the first human study to
examine the role of exercise in countering the potential detrimental effects of this weight regain on MetS variables and
overall health status. This model offers unique potential for
studying weight regain in humans. In conjunction with a
relatively standard aerobic exercise prescription, we were able
to titrate caloric intake using daily food records and weekly
dietary counseling to achieve an individualized controlled
weight regain program.
In conclusion, the results of this study suggest that exercise
may counter the detrimental effects of partial weight gain on
many markers of metabolic health and disease risk. In contrast,

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after a training program comparable to ours. On the other hand,

the increased HDL-C also could result from the increased total
cholesterol concentration observed during the regain period.
In contrast to most outcome variables, exercise did not
maintain the improvements in abdominal fat, cholesterol, or
TG concentrations. The lack of maintenance in TG and cholesterol concentrations in the EX group was most likely due to
the increased intake of cholesterol, saturated fat, and trans fat,
PWL vs. PWR (Table 2). Aerobic exercise has been shown to
have a potent impact on reducing abdominal fat (15, 25).
However, exercise training had virtually no impact on maintaining the reductions in abdominal adiposity during the weight
regain period (Fig. 5). This unexpected finding could be due to
differences in the weight changes among studies. In previous
studies there was an extended period of energy balance (29) or
energy deficit (15), whereas participants in the present study
were in a state of positive energy balance during the weight
regain phase. These results suggest that the ingestion of excess
energy can result in adipose fat accumulation in the abdomen
despite concomitant exercise training.
Reductions in abdominal adiposity have been linked to
improvements in other metabolic variables, most notably insulin sensitivity (11, 15), suggesting that changes in insulin
sensitivity and abdominal adiposity would occur in parallel
during weight regain. However, these two variables did not
change equally during the weight regain period in the EX
group. This result suggests that other factors related to exercise
O2max) or
training, such as improved cardiovascular fitness (V
reduced systemic inflammation (oxLDL, TNF-), may be
driving the maintained improvement in insulin sensitivity during weight regain. Regardless, the results of the present study
suggest that it is necessary to maintain reduced body weight to
stabilize reduced abdominal fat stores.
The danger of weight regain without exercise is highlighted in
the present study. In the NoEX group, the weight loss-induced
benefits to metabolic parameters were rapidly lost. That is, in the
absence of exercise, even partial weight regain produced significant detriment in health status within a 6-mo period. It may be
noteworthy that several markers were back to near pre-study
values, i.e., the PWR value was not significantly different from
baseline (e.g., SBP and DBP, HOMA, and oxLDL) even though
only half the weight was regained. In another study, 12 women
who participated in 16 wk of aerobic training and then detrained
for 6 wk regained all the lost body weight (4.9% body weight) and
exhibited complete return of the lipoprotein profile to baseline
values (18). In addition, recent work on rodents demonstrated that
weight regain was caused in part by weight loss-induced metabolic aberrations that were normalized in a group undergoing
exercise training (19). The possibility also exists that the negative
health changes in outcome measures during weight regain in
NoEX could have been due to the cessation of exercise training,
not necessarily solely due to weight regain. In support of the
detraining concept, results from a recent report demonstrated
that reduced activity had a negative impact on metabolic health
even without weight gain (23).
Although the results point to the ability of exercise to maintain
the metabolic effects of weight loss, the magnitude of the effect is
debatable. In most cases, the NoEX group exhibited deterioration
in metabolic markers, while the EX group maintained these
parameters during regain. However, except for DBP and insulin
concentration, the NoEX and EX groups were not significantly

10

EXERCISE AND WEIGHT REGAIN

weight regain without exercise produces generally detrimental

effects on these markers.
ACKNOWLEDGMENTS
We thank Joseph Donnelley, EdD, James Sowers, MD, and Craig Stump,
MD, PhD, for input and participation during study planning and initiation. We
also thank Junor Chelif, MD, and Guru Govindarajan, MD, for assistance in
supervising stress tests, and Thomas P. LaFontaine, PhD, for serving as the
project safety officer. We greatly appreciate the work of the many graduate
students who served as personal trainers and monitors for the subjects.
GRANTS
This study was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grant R01-DK-067036 and National Heart, Lung, and
Blood Institute Grant T32-AR-048523.
DISCLOSURES
No conflicts of interest (financial or otherwise) are declared by the authors.
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