J Appl Physiol 112: 79–85, 2012.
First published October 20, 2011; doi:10.1152/japplphysiol.00355.2011.
Preferential reductions in intermuscular and visceral adipose tissue with
exercise-induced weight loss compared with calorie restriction
Joan C. Murphy,1 Jennifer L. McDaniel,1 Katherine Mora,1 Dennis T. Villareal,2 Luigi Fontana,2,3
and Edward P. Weiss1,2
1
Department of Nutrition and Dietetics, Doisy College of Health Sciences, Saint Louis University, St. Louis; 2Department of
Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri;
and 3Division of Food Science, Human Nutrition and Health, Istituto Superiore di Sanita, Rome, Italy
Submitted 25 March 2011; accepted in final form 17 October 2011
Murphy JC, McDaniel JL, Mora K, Villareal DT, Fontana L,
Weiss EP. Preferential reductions in intermuscular and visceral adi-
pose tissue with exercise-induced weight loss compared with calorie
restriction. J Appl Physiol 112: 79 – 85, 2012. First published October
20, 2011; doi:10.1152/japplphysiol.00355.2011.—Intermuscular adi-
pose tissue (IMAT) and visceral adipose tissue (VAT) are associated
with insulin resistance. We sought to determine whether exercise-
induced weight loss (EX) results in greater reductions in IMAT and
VAT compared with similar weight loss induced by calorie restriction
(CR) and whether these changes are associated with improvements in
glucoregulation. Sedentary men and women (50 – 60 yr; body mass
index of 23.5–29.9 kg/m2) were randomized to 1 yr of CR (n ⫽ 17),
EX (n ⫽ 16), or a control group (CON; n ⫽ 6). Bilateral thigh IMAT
and VAT volumes were quantified using multi-slice magnetic reso-
nance imaging. Insulin sensitivity index (ISI) was determined from
oral glucose tolerance test glucose and insulin levels. Weight loss was
comparable (P ⫽ 0.25) in the CR (⫺10.8 ⫾ 1.4%) and EX groups
(⫺8.3 ⫾ 1.5%) and greater than in the control group (⫺2.0 ⫾ 2.4%;
P ⬍ 0.05). IMAT and VAT reductions were larger in the CR and EX
groups than in the CON group (P ⱕ 0.05). After controlling for
differences in total fat mass change between the CR and EX groups,
IMAT and VAT reductions were nearly twofold greater (P ⱕ 0.05) in
the EX group than in the CR group (IMAT: ⫺45 ⫾
5 vs. ⫺25 ⫾ 5 ml; VAT: ⫺490 ⫾ 64 vs. ⫺267 ⫾ 61 ml). In the EX
group, the reductions in IMAT were correlated with increases in ISI
(r ⫽ ⫺0.71; P ⫽ 0.003), whereas in the CR group, VAT reductions
were correlated with increases in ISI (r ⫽ ⫺0.64; P ⫽ 0.006). In
conclusion, calorie restriction and exercise-induced weight loss both
decrease IMAT and VAT volumes. However, exercise appears to
result in preferential reductions in these fat depots.
calorie restriction; exercise; weight loss; insulin resistance; muscle fat
infiltration
INTERMUSCULAR ADIPOSE TISSUE (IMAT) is adipose tissue (i.e.,
adipocytes) that is interspersed between muscle cells and
bundles and within the boundary of the whole muscle, as
defined by the epimysium fascia. Cross-sectional studies have
shown that IMAT is a strong determinant of insulin resistance,
possibly as good a marker as visceral adipose tissue and better
than whole-body fat mass (4). Intervention studies have shown
that decreases in whole-body and visceral adipose tissue are
associated with decreases in insulin resistance (13); however, it
is not clear whether reductions in IMAT are associated with
decreases in insulin resistance.
Address for reprint requests and other correspondence: E. P. Weiss, Dept. of
Nutrition and Dietetics, Saint Louis Univ., 3437 Caroline St., Rm. 3076, St.
Louis, MO 63104 (e-mail: eweiss4@slu.edu).
http://www.jap.org 8750-7587/12 Copyright © 2012 the American Physiological Society
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Calorie restriction (CR) and exercise (EX), when sufficient
in volume (i.e., 60 min of daily vigorous cardiovascular exer-
cise) both result in weight loss and improve glucoregulatory
function (24, 25, 30). However, it is not known whether one of
these approaches to weight loss leads to greater reductions in
IMAT. Single-leg immobilization in humans has been shown
to increase IMAT volume in as little as 4 wk (18). Furthermore,
physical activity has been shown to protect against age-depen-
dent accumulation of IMAT (15). Therefore, it is conceivable
that, with similar reductions in whole-body fat mass, EX could
result in greater reductions in IMAT compared with CR.
The primary purpose of the present study was to test the
hypothesis that both CR- and EX-induced weight loss decrease
IMAT volumes but that EX results in greater reductions when
changes in whole-body fat mass are similar. Additionally, we
had previously reported that EX does not result in a preferential
loss of VAT compared with CR (23). However, in that report,
we did not account for small but important differences between
groups in total fat mass; therefore, a secondary purpose of the
present study was to determine whether EX results in prefer-
ential VAT reductions after statistically adjusting for small
differences in total body fat mass. The data reported in this
article were obtained as part of an investigation [Phase I
Comprehensive Assessment of Long-term Effects of Reducing
Intake of Energy (CALERIE)] of the feasibility of long-term
CR on potential markers of aging and risk factors for age-
related disease. This paper reports site-specific findings from
the Washington University site of the CALERIE studies. Other
results from this study have been published previously (23, 27,
29 –31).
METHODS
Participants. Men and postmenopausal women aged 50 – 60 yr with
a body mass index of 23.5–29.9 kg/m2 were recruited from the St.
Louis, MO, metropolitan area. Potential subjects were excluded if
they had a history of diabetes or fasting blood glucose value of ⱖ126
mg/dl or a resting blood pressure of ⬎170 mmHg systolic or ⬎100
mmHg diastolic. Other exclusion criteria included a history or clinical
evidence of coronary artery disease, stroke, or lung disease as well as
a recent history or evidence of malignancy. Subjects had to be
nonsmokers and sedentary (defined as exercising ⬍20 min/day, twice
per week during the 6 mo before baseline testing). Participants were
randomly assigned with stratification for sex to 12 mo of CR, EX, or
to “healthy lifestyle” control group (CON). All participants gave their
informed, written consent to participate in the study, which was
approved by the Human Research Protection Committee at Washing-
ton University School of Medicine.
CR intervention. The objective of the CR intervention was for
participants to decrease calorie intake by 16% during the first 3 mo
79
80 CALORIE RESTRICTION, EXERCISE, AND IMAT
and by 20% during the remaining 9 mo. Prescriptions were based on
total daily energy intake, which was assumed to equal total daily
energy expenditure as measured by using doubly labeled water over
two consecutive 2-wk assessment periods (methodology described
below). Participants met with study dietitians once a week for body
weight checks and for education on reducing portion sizes and
replacing high-energy density foods with lower energy density foods.
The participants kept diaries of their food intake on a regular basis
during the study; information from the diaries was used by the
dietitians as the basis for dietary counseling and for subjective
monitoring of the subjects’ progress.
EX intervention. The EX intervention was designed to induce the
same energy deficit as was induced by the CR intervention. Thus
participants increased their energy expenditure from baseline by 16%
during the first 3 mo and by 20% during the remaining 9 mo.
Prescriptions were based on total daily energy expenditure assess-
ments performed by using doubly labeled water as described below.
Participants met with an exercise trainer on a weekly basis, and
exercise energy expenditure goals were established at this time.
Subjects were encouraged to use cardiovascular exercise as the most
time-efficient approach to meeting the energy expenditure prescrip-
tions. Participants were able to exercise at the site’s facility or on their
own with no specifications for frequency, duration, or intensity.
Participants used heart rate monitors to measure and record daily and
weekly gross exercise energy expenditure, exercise duration, and exercise
heart rate. Heart rate monitor data were downloaded and reviewed each
week by the exercise trainers to determine compliance. Exercise compli-
ance data are presented in RESULTS below.
CON intervention. Participants in the CON group had minimal
contact with the research team and were not provided with a diet or
exercise prescription. General information on a healthy diet was
provided if requested by the participants, and free access to yoga
classes was provided in the form of class passes/vouchers. Although
requests for dietary advice and yoga class passes were not docu-
mented and/or quantified, requests for these benefits were minimal.
Doubly labeled water assessments of total energy expenditure.
Doubly labeled water (DLW) assessments were used to assess total
energy expenditure (TEE) at baseline and served as the basis for the
calculated goal for increases in TEE (i.e., 16 –20% increase) in the EX
group. Because the subjects were weight stable during the DLW
assessment period, baseline energy intake was assumed to equal TEE,
and this was used as the basis for calculating the goal for reductions
in energy intake (i.e., 16 –20% decrease) in the CR group. DLW
assessments were made after two baseline urine samples were ob-
tained and then an oral dose of DLW was administered (0.20 g of
H218O, 0.12 g of 2H2O per kilogram of total body water); total body
water was determined by using bioelectrical impedance. Urine sam-
ples were collected 4.5 h, 6 h, 7 days, and 14 days after dosage and
were measured in duplicate for isotope abundance by using isotope
ratio mass spectrometry.
Anthropometry and body composition. Body weight was measured
in duplicate in the morning after an overnight fast with the
participant only wearing underwear and a hospital gown. Body
weight for each assessment period (i.e., baseline and 12 mo) was
calculated as the average of measures made on 3–5 different days.
Height was measured to the nearest 0.1 cm at baseline. Fat mass,
fat-free mass, and percentage body fat were measured with dual-
energy X-ray absorptiometry (DXA) (Delphi W, Hologic,
Waltham, MA; software version 11.2).
Abdominal visceral adipose tissue (VAT) and subcutaneous
adipose tissue (SAT) were measured with magnetic resonance
imaging (MRI; Siemens, Iselin, NJ) using 10 serial 10-mm axial
images beginning at L1 and moving downward. Images were
analyzed with HIPPO software (version 1.3; Pisa, Italy) (21), and
slice fat volumes were summed to give total visceral and subcu-
taneous adipose tissue volumes. Additional methodological details
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for MRI image acquisition and analysis for our laboratory have
been previously reported (1, 23).
Thigh adipose tissue volumes were quantified by using MRI. Ten
transverse images, 10 mm thick, were obtained just superior to the
patella with no intersection gap between slices with a 1.5-T super-
conducting MRI instrument (Siemens, Iselin, NJ) and a T1-weighted
pulse sequence. Subcutaneous adipose tissue and IMAT volumes of
the thighs were quantified using Analyze Direct software (version
10.0; Mayo Clinic, Rochester, MN), which distinguishes muscle from
adipose tissue based on pixel brightness. The technician manually
designated the boundary between muscle and subcutaneous compart-
ments by tracing the muscle fascia (epimysium) on the MR image; by
using a similar method, the bone area was excluded from further
analysis. Then, a bright white pixel known to be fat was designated as
such by planting a “seed” in that region. The software then identified
all other pixels of equal or greater brightness as fat and summed the
pixel area as an estimate of two-dimensional fat area. As needed based
on visual inspection of the selected fat regions, the technician adjusted
the brightness threshold, thereby allowing the software to better
capture and quantify fat regions and/or exclude nonfat regions. Cross-
sectional areas for each slice were multiplied by slice thickness to
obtain volume data. Volume data from the most proximal eight slices
were summed to give thigh adipose tissue volumes in the 8-cm region
of interest. All thigh adipose tissue volumes are reported as the sum
of the right and left thighs.
Oral-glucose-tolerance test and fasting blood analyses. Two-hour,
75-g oral glucose tolerance tests (OGTTs) were performed in the
morning after a 12-h fast. Subjects were advised to refrain from
exercise for ⱖ48 h before the OGTT. Additionally, subjects were
given specific instructions by the study dietitian to consume at least 11
servings per day of carbohydrate-rich foods (i.e., fruits, breads, and/or
dairy equivalent to ⱖ150 g/day carbohydrate) for 3 days before the
OGTT but were otherwise advised to maintain their usual diet; small
or moderated amounts of alcohol and caffeine were permitted if it was
part of the subject’s habitual diet. At 1600 –1800 in the evening before
the OGTT, the participants were admitted to the General Clinical
Research Center and ate a standardized evening meal, which did not
contain alcohol or caffeine. Thereafter, nothing was consumed except
water until the OGTT commenced the next morning. Blood samples
were acquired before and every 30 min after ingestion of the glucose
beverage. Plasma glucose was measured with the glucose oxidase
method (YSI Stat Plus; YSI, Yellow Springs, OH). Plasma insulin was
measured with a double-antibody radioimmunoassay. Total areas
under the curve (AUCs) were calculated for the plasma glucose and
insulin responses using the trapezoidal rule. Insulin sensitivity index
was calculated according to Matsuda and Defronzo (19) and was
based on all measures of glucose and insulin made during the OGTT.
Statistical analyses. Analyses were performed with data from all
subjects who underwent both baseline and 12-mo thigh MRI scans.
Baseline characteristics were compared by using ANOVA for quan-
titative measures and by using Fisher’s exact tests for categorical
variables. Study outcomes were analyzed by using analysis of cova-
riance (ANCOVA) in which change scores (i.e., final minus initial
values) were used as the dependent variable, study group was used as
the independent variable, and baseline values were included as a
covariate. Because there were small (but nonsignificant) differences in
fat mass changes between the CR and EX groups (indicating differ-
ences between groups in terms of the year-long energy deficit),
additional ANCOVA analyses were performed, which included only
the CR and EX groups; in addition to the baseline values, fat mass
change was included as a covariate in these analyses so that the effects
of the CR and EX interventions on outcomes could be evaluated as if
fat mass changes were identical. Furthermore, although our sample
size was not optimal for including additional covariates, we also
performed exploratory analyses that included age and sex as covari-
ates. Post hoc paired comparisons were performed by using least
significant difference (protected F test). Parametric correlation anal-
 CALORIE RESTRICTION, EXERCISE, AND IMAT
yses were performed by using Pearson’s correlations to determine
relationships among outcomes that changed in response to the inter-
ventions; non-parametric Spearman rank correlation analyses were
also performed, since it was questionable whether some of the data
distributions were suitable for parametric analyses. Analyses were
performed with SAS for Windows version 9.2. All statistical tests
were two-tailed, and significance was accepted at P ⱕ 0.05. Data are
reported as means ⫾ SE unless otherwise noted.
RESULTS
Participants. Forty-eight participants started the study and
were randomized to CR (n ⫽ 19), EX (n ⫽ 19), or CON (n ⫽
10). Two subjects (CR, n ⫽ 1; EX, n ⫽ 1) dropped out before
undergoing follow-up testing. Furthermore, seven subjects
(CR, n ⫽ 1; EX, n ⫽ 2; CON, n ⫽ 4) were not included in the
present report because of missing MRI data due to technical
problems, participant refusal to undergo the MRI scan, or
inability to perform MRI scans on participants with metallic
implants or prostheses. Therefore, data from 39 subjects were
included in the present analysis.
Sex and racial distributions were similar in all groups as
presented in Table 1. On average, subjects in the exercise
group were slightly older than in the other groups (Table 1).
Average body mass index values were in the overweight range
for all groups. Baseline values for whole-body and regional
body composition did not differ between groups (Table 1).
Compliance. Compliance data have been previously re-
ported in greater detail (23, 30). The average prescribed in-
crease in physical activity energy expenditure in the EX group
was 563 kcal/day. Based on measured 7-day physical activity
recall questionnaires, physical activity energy expenditure in-
creased by 408 kcal/day (P ⱕ 0.05) during the EX intervention
and did not change significantly in the CR (⫺93 kcal/day) or
CON (⫹128 kcal/day) groups. Based on data retrieved from
portable heart rate monitors, the EX group participants exer-
cised 6 days/wk for 62 min/session at 71% of maximal heart
rate; this corresponded with a net exercise energy expenditure
of 228 kcal/day, which is likely an underestimate because
⬃14% of the exercise session were not recorded on the heart
rate monitors. The most frequently used modes of exercise
81
were walking, elliptical machine exercise, cycling, and run-
ning. On average, the prescribed reduction in energy intake for
participants in the CR group was 524 kcal/day. According to
7-day food diaries, energy intake in the CR group decreased by
⬃318 kcal/day (P ⬍ 0.05) during the intervention and did not
change in the EX (⫹48 kcal/day) or CON (⫺44 kcal/day)
groups.
Body weight and composition. Body weight, whole-body
adiposity, and abdominal adiposity data have been reported
previously (23, 28) but are presented here (Table 1; Fig. 1) for
the smaller subset of subjects used in the present report to assist
in interpreting the IMAT data. Body weight, whole body
adiposity, and VAT decreased significantly in the CR and EX
groups but did not change in the CON group. SAT decreased
in the CR and EX groups; however, only the CR group changes
were significantly different from those in the CON group (Fig.
1). Thigh IMAT volume decreased significantly in the EX and
CR groups and remained unchanged in the control group (Fig.
1, bottom). Thigh subcutaneous fat volume decreased signifi-
cantly in the EX and CR groups; however, only the change in
the CR group differed significantly from that for the CON
group (Fig. 1, bottom). None of these findings was affected by
the inclusion of age and sex as covariates in the analyses except
for the VAT comparisons in which the ANCOVA P value
became 0.06, likely due to the loss of statistical power resulting
from the added covariates.
Although the reductions in whole body fat mass in the CR
and EX groups were not significantly different, there were
somewhat greater fat mass reductions in the CR group. There-
fore, additional analyses of the changes in VAT and IMAT
were performed in an analysis that only included the CR and
EX groups and included changes in whole-body fat mass as a
covariate. After adjusting for differences in whole-body fat
mass reductions, the EX group had twofold greater reductions
in VAT and IMAT compared with the CR group (Fig. 2). The
addition of age and sex as covariates did not alter the signifi-
cance of these findings. Furthermore, although our study was
not optimally powered to evaluate differential changes in VAT
and IMAT between men and women, we saw no evidence for

Table 1. Baseline characteristics of the Study Participants

Calorie Restriction (n ⫽ 17) Exercise (n ⫽ 16) Control (n ⫽ 6) P Value

Sex
Men 6 (35%) 6 (38%) 2 (33%) 1.00
Women 11 (65%) 10 (62%) 4 (67%)
Race
White 16 (94%) 15 (94%) 5 (83%) 0.54
Other 1 (6%) 1 (6%) 1 (17%)
Age, yr 55.0 ⫾ 0.7 59.0 ⫾ 0.7* 55.7 ⫾ 1.2 0.0009
Weight, kg 78.1 ⫾ 2.5 76.8 ⫾ 2.6 81.2 ⫾ 4.2 0.68
BMI, kg/m2 26.7 ⫾ 0.5 26.8 ⫾ 0.5 27.2 ⫾ 0.8 0.88
Total fat mass, kg 26.8 ⫾ 1.3 25.3 ⫾ 1.4 25.9 ⫾ 2.3 0.73
Percent body fat, % 35.1 ⫾ 1.9 33.8 ⫾ 2.0 33.1 ⫾ 3.3 0.84
Abdominal VAT, ml 828 ⫾ 136 1126 ⫾ 140 1158 ⫾ 228 0.25
Abdominal SAT, ml 2455 ⫾ 134 1920 ⫾ 138 1833 ⫾ 225 0.34
Thigh IMAT, ml 108 ⫾ 9 96 ⫾ 9 77 ⫾ 15 0.25
Thigh subcutaneous fat, ml 971 ⫾ 90 845 ⫾ 93 882 ⫾ 152 0.62
Thigh muscle volume, ml 1233 ⫾ 210 1582 ⫾ 216 1301 ⫾ 354 0.50
Values for sex and race are frequencies, with percentage of the group in parentheses; all other values are means ⫾ SE. P values for categorical measures are
from Fisher’s exact tests. P values for quantitative measures are from 1-way ANOVAs. BMI, body mass index; VAT, visceral adipose tissue; SAT, subcutaneous
adipose tissue; IMAT, intermuscular adipose tissue. *Significant difference vs. calorie restriction and control groups based on post hoc least significant difference
tests (P ⱕ 0.05).

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82 CALORIE RESTRICTION, EXERCISE, AND IMAT
Fig. 1. Changes in body weight and composition in response to 12 mo of
weight loss induced by calorie restriction or exercise and in the control group.
Values are means ⫾ SE and have been adjusted for baseline values. CR,
calorie restriction group; EX, exercise-induced weight loss group; CON,
control group; VAT, visceral adipose tissue volume; SAT, subcutaneous
adipose tissue volume; IMAT, thigh intermuscular adipose tissue volume;
SCAT, thigh subcutaneous adipose tissue volume.
differential effects in men and women (study group by sex
interaction effects: VAT, P ⫽ 0.76; IMAT, P ⫽ 0.87).
Insulin action and oral glucose tolerance. Changes in insu-
lin action have been previously presented (30) but are pre-
sented briefly here for the slightly smaller sample used in the
present study (Fig. 3). OGTT glucose AUC decreased in the
CR and EX groups and remained unchanged in the CON
group. These reductions in postprandial glucose concentrations
occurred despite lower fasting and postprandial insulinemia in
Fig. 2. Abdominal and thigh adipose tissue volumes in response to 12 mo of
calorie restriction or exercise-induced weight loss. Values are means ⫾ SE and
have been adjusted for baseline values and for between-group differences in
total fat mass reductions.
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Fig. 3. Changes in indexes of glucoregulatory function in response to calorie
restriction and exercise-induced weight loss, and in the control group. Values
are means ⫾ SE and have been adjusted for baseline values. Insulin sensitivity
index values were log transformed for statistical analysis; however, untrans-
formed, baseline-adjusted means are presented for ease of interpretation. AUC,
area under the curve during the 2-h oral glucose tolerance test.
the CR and EX groups. Accordingly, insulin sensitivity index
increased in the EX and CR groups but did not change in the
CON group (Fig. 3). These findings were not altered by the
inclusion of age and sex as covariates.
Correlations. At baseline for all groups combined, higher
levels of VAT were associated with lower ISI (r ⫽ ⫺0.63;
P ⫽ 0.0001). In contrast, baseline IMAT values (all groups
combined) were not correlated with ISI (r ⫽ ⫺0.21; P ⫽ 0.25).
In response to the CR intervention, reductions in VAT but not
IMAT changes were correlated with increases in ISI (Fig. 4). In
response to the EX intervention, there was a marginal (but
nonsignificant) association between VAT reductions and im-
provements in ISI (Fig. 4). However, decreases in IMAT in the
EX group were strongly associated with increases in ISI (Fig.
4). Because of outlier values in the data used for correlation
analyses (Fig. 4), non-parametric Spearman rank correlation
analyses were also performed. The marginal correlation in the
EX group between changes in VAT and improvements in ISI
became more clearly nonsignificant (P ⫽ 0.12). The signifi-
cance/nonsignificance of all other correlations was not altered
by performing non-parametric analyses.
DISCUSSION
Findings from the present study indicate that both CR and
EX-induced weight loss result in decreases in intermuscular
adipose tissue volume in the thigh muscles. However, when
matched for reductions in total body fat mass, exercise results
in a substantially larger reduction in thigh IMAT volume.
Furthermore, we had previously reported that visceral adipose
tissue volume decreases similarly in response to CR and
EX-induced weight loss (23). However, there were small
differences between the CR and EX groups with respect to
whole body fat mass reductions. In the present study, after
statistically accounting for whole body fat mass changes, the
reductions in VAT in response to exercise-induced weight loss
were significantly greater than those seen in response to CR.
Taken together, these results indicate that exercise results in
preferential reductions in thigh IMAT and VAT compared with
CR, provided that the exercise volume is sufficient to induce
weight loss. These findings add to existing literature in show-
 CALORIE RESTRICTION, EXERCISE, AND IMAT
ing that, at least for some outcomes, exercise may provide
larger benefits than those which are attainable through CR
alone (11, 29).
Other studies support the notion that exercise affects IMAT
levels, independent of changes in whole body mass. For ex-
ample, 4 wk of single leg immobilization in healthy humans,
which was accomplished by having the subjects use crutches to
make one leg non-weight-bearing, resulted in increases in
IMAT in the immobilized limb despite a small but significant
reduction in whole body mass (18). In another study, a year-
long physical activity intervention that included cardiovascu-
lar, strength, and balance exercises protected 70- to 89-yr-old
men and women from increases in IMAT, as were seen in the
nonexercising control group, despite no differences between
groups with respect to changes in whole-body mass (15). In
contrast, another study reported that an intervention of CR and
EX, compared with similar body mass and fat mass reductions
induced by CR alone, did not result in significantly greater
reductions in IMAT (although the absolute IMAT reduction
was ⬃70% greater in the combined intervention group) (5).
However, the exercise volume (3 days/wk, 60 –75 min/session)
was approximately half of that used in the present study and
may not have been sufficient for large effects on body weight
and composition.
Acute vigorous exercise stimulates lipolysis in adipocytes
through increases in sympathetic adrenergic activity (3, 17,
32). Although this effect is systemic, visceral adipose tissue is
especially sensitive to lipolytic activation by the adrenal sys-
tem (2). Therefore, it seems plausible that the exercise-induced
adrenal activity is at least partly responsible for the preferential
reductions in VAT seen in our study. Whether this contributes
to preferential reductions in IMAT induced by exercise is not
clear, since it is not known whether IMAT, like VAT, has high
sensitivity to adrenergic lipolytic activation. However, from a
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83
Fig. 4. Associations between changes in vis-
ceral or intermuscular adipose tissue volume
and changes in insulin sensitivity index in the
calorie restriction and exercise groups. Corre-
lation coefficients are from Pearson correla-
tions. Because of several outlier values, non-
parametric Spearman rank correlation analy-
ses were also performed. The marginally
significant correlation between changes in
VAT and improvements in ISI in the EX
group (top right) became more clearly non-
significant (P ⫽ 0.12). The significance/non-
significance of all other correlations was not
altered by performing non-parametric analy-
ses.
biological perspective, it is logical that IMAT would serve as
an energy source for contracting muscle because of its prox-
imity to muscle cells. If this is the case, repeated bouts of
exercise would be expected to decrease IMAT volume in active
muscle, whereas IMAT in inactive muscle would remain un-
changed. Future studies might be able to gain insights into this
possibility by comparing changes in IMAT in active vs. inac-
tive muscles during exercise-induced weight loss.
It seems likely that some of the improvements in insulin
action seen in both the CR and EX groups were mediated by
reductions in whole-body and/or regional adiposity. However,
it is surprising that the larger reductions in VAT and IMAT
seen in the exercise group were not associated with greater
improvements in insulin action. This is even more perplexing
when considering that exercise improves glucoregulation, even
in the absence of weight loss (7, 8), although this weight
loss-independent effect is likely acute and might have dissi-
pated in the ⱖ48 h between the last exercise bout and the
OGTT (16, 20). Several explanations are possible. First, it is
possible that the glucoregulatory benefit of a greater reduction
in VAT and IMAT in the exercise group was matched by a
CR-specific effect. That is, although the overall improvements
in glucoregulation in the CR and EX groups were similar, the
improvements may have occurred through partly different
mechanisms. Limited evidence for differential adaptive mech-
anisms between CR and EX comes from the correlation anal-
yses in the present study, showing that the improvements in
insulin action in the CR group were more tightly associated
with VAT changes, whereas those in the EX group were more
tightly associated with IMAT changes. To gain further insights
into mechanistic differences between adaptations to CR and
EX, we are currently performing a trial to determine whether
CR, but not comparable weight loss through exercise, improves
glucoregulation by altering postprandial incretin hormone re-
84 CALORIE RESTRICTION, EXERCISE, AND IMAT
sponses [i.e., GIP and/or GLP-1, both of which are involved in
glycemic control (9)].
Another explanation for the similar improvements in gluco-
regulation in the CR and EX groups, despite greater exercise-
induced improvements in VAT and IMAT, is that there is no
mechanistic link (i.e., cause-effect relationship) between glu-
coregulation and VAT and IMAT. Although this notion con-
tradicts dogma, especially for VAT, research has shown that
there is no difference in insulin sensitivity between subjects
with low VAT volumes and those with a twofold greater VAT
volume when the low and high VAT groups were matched for
intrahepatic triglyceride content (10), implying no mechanistic
connection between VAT and glucoregulation.
Although it is commonly thought that fat is a regulator of
insulin action, inflammation, and oxidative stress, it has been
proposed that the opposite is true for IMAT. That is, insulin
resistance, inflammation, and oxidative stress regulate IMAT
accumulation through effects on adipogenesis (26). The fact
that we did not observe differences in insulin action and
markers of systemic inflammation [i.e., IL-6, TNF-␣, C-reac-
tive protein, and free fatty acids, as published previously (12,
30)] whereas we did see differences in IMAT changes between
groups argues against this possibility. Furthermore, it seems
unlikely that alterations in adipogenesis could explain the
differential effects of CR and EX on IMAT, since our subjects
were in a net energy deficit, thereby making any effects on
adipogenesis, which is an anabolic state, unlikely.
In conclusion, 1 year of exercise-induced weight loss results
in greater reductions in IMAT and VAT than comparable
weight loss induced by CR alone. Although this advantage of
exercise-induced weight loss did not coincide with greater
improvements in glucoregulation, these findings raise the pos-
sibility that CR and EX improve glucoregulation through partly
distinct mechanisms, some of which do not involve VAT and
IMAT. Furthermore, because VAT and IMAT have been
linked to other outcomes such as oxidative stress (14, 22) and
muscle contractile function (6, 18), respectively, it is possible
that exercise-induced weight loss may have other advantages
over CR alone.
ACKNOWLEDGMENTS
We are grateful to the study participants for cooperation and to the staff of
the Applied Physiology Laboratory and the General Clinical Research Center
at Washington University School of Medicine for skilled assistance.
GRANTS
This work was supported by National Institutes of Health Cooperative
Agreement AG-20487, National Institutes of Health General Clinical Research
Center Grant RR-00036, National Institute of Diabetes and Digestive and
Kidney Diseases Research Training Center Grant DK-20579, and National
Institute of Diabetes and Digestive and Kidney Diseases Clinical Nutrition
Research Unit Grant DK-56341. E. P. Weiss was supported by National
Institute on Aging Grant AG-00078 and National Institute of Diabetes and
Digestive and Kidney Diseases Grant DK-080886.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: J.C.M., J.L.M., K.M., D.T.V., L.F., and E.P.W.
conceptualized and designed the research; J.C.M. and E.P.W. performed
experiments; J.C.M. and E.P.W. analyzed data; J.C.M., J.L.M., K.M., D.T.V.,
L.F., and E.P.W. interpreted results of experiments; J.C.M. and E.P.W.
J Appl Physiol • doi:10.1152/japplphysiol.00355.2011 • www.jap.org
Downloaded from www.physiology.org/journal/jappl at Univ of Sydney 1370765 (129.078.139.029) on January 22, 2020.
prepared figures; J.C.M. and E.P.W. drafted the manuscript; J.C.M., J.L.M.,
K.M., D.T.V., L.F., and E.P.W. edited and revised the manuscript; J.C.M.,
J.L.M., K.M., D.T.V., L.F., and E.P.W. approved the final version of manu-
script.
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