nature publishing group articles

Physical activity and cardiovascular risk

Exercise, Abdominal Obesity,

Skeletal Muscle, and Metabolic Risk:
Evidence for a Dose Response
Cris A. Slentz1, Joseph A. Houmard2 and William E. Kraus1,3

The obese are at increased risk for cardiovascular disease and type 2 diabetes. However, some who are obese
have no metabolic abnormalities. So, it is not adipose tissue per se, but perhaps where it is located that is important
for determining metabolic consequences. Regular exercise is known to reduce risk for metabolic disease through
numerous mechanisms. The purpose of this report is to highlight some of the efficacy-based data on the effects of
exercise (and also a sedentary lifestyle) on abdominal obesity, visceral fat, and metabolic risk. We also discuss how
impaired fatty acid oxidation (FAO) in skeletal muscle may be related to both insulin resistance and a contributor
to weight gain. In summary, it is evident that exercise in sufficient amounts can lead to substantial decreases
in body weight, total body fat, and visceral fat. Additionally, evidence now supports the conclusion that there is
a dose–response relationship between exercise amount and these changes, i.e., more exercise leads to additional
benefits. Additionally, there are a number of important cardiometabolic risk factors that were most favorably effected
by moderate-intensity compared to vigorous-intensity exercise. Unfortunately, it is also apparent that in sedentary
middle-aged men and women, short periods of physical inactivity lead to significant weight gain, substantial increases
in visceral fat, and further metabolic deterioration. Finally, favorable modulation of mitochondrial oxidative capacity
in skeletal muscle by exercise training may reduce a block for complete oxidation of fatty acids in muscle and thereby
relieve a block to effective insulin signaling.

In general, individuals who are obese are at increased risk for
cardiovascular disease and type 2 diabetes. However, some
individuals who are obese have no metabolic abnormalities,
such as insulin resistance. It is clear that it is not fat or adipose
tissue per se that is the issue, but perhaps where the fat is located
that is important for determining dysmetabolic consequences.
Research has firmly established that abdominal obesity (1) and
especially increased levels of visceral fat (2–5) are more highly
associated with metabolic disease risk.
Regular exercise is known to reduce risk for cardiovascular
disease and type 2 diabetes through numerous mechanisms. It
reliably and robustly improves insulin sensitivity and cardio-
vascular fitness (6,7), reduces blood pressure (8,9), improves
dyslipidemia (10,11), and both individual and combined fac-
tors of metabolic syndrome score (12,13). Regular exercise
has modest effects on reducing body weight with substantially
greater effects on improving body composition. Conversely, it
is becoming increasingly clear that a continued sedentary life-
style in overweight or obese individuals—particularly those
who already have some metabolic abnormalities—comes at
a high metabolic cost, as numerous health-related variables
worsen over relatively short time periods (12,14–16).
1
Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; 2Department of Exercise & Sports Science,
Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA; 3Division of Duke Center for Living, Duke University Medical Center, Durham,
North Carolina, USA. Correspondence: Cris A. Slentz (Cris.Slentz@duke.edu)
The purpose of this report is to highlight some of efficacy-
based data on the effects of exercise (and also of continued
inactivity) on abdominal obesity, visceral fat, and health-
related metabolic risk variables. In addition to the impor-
tant role of upper body obesity, we also briefly discuss how
impaired fatty acid oxidation (FAO) in skeletal muscle may be
related to both insulin resistance and a contributor to risk of
weight gain.
The Short-Term Detrimental Effects
of Physical Inactivity
A sedentary lifestyle over several years is associated with
increased risk for type 2 diabetes, cardiovascular disease, and
premature mortality (17–20). What is much less appreciated
is the high cost of physical inactivity even in the short term.
Booth et al. have been drawing attention for years to the soci-
etal and individual burden of inactivity-related chronic diseases
(15,21,22). They remind us that while exercise is a treatment to
prevent many chronic diseases, it is the lack of regular exer-
cise or physical inactivity that is one of the actual causes of
many of these diseases. Particularly relevant to this review,
Booth’s group recently reported that cessation of ­exercise led to

obesity | VOLUME 17 SUPPLEMENT 3 | DECEMBER 2009 S27

articles
s­ ignificant increases in intra-abdominal fat within just 21 days
in an animal model (23).
In (Studies Targeting Risk Reduction Intervention through
Defined Exercise—a randomized, controlled trial) we stud-
ied the effects of different amounts and intensities of exercise
training for ~8 months on numerous cardiometabolic risk fac-
tors. It soon became obvious that there were numerous det-
rimental effects accruing in the inactive control group over
only 6 months. We observed small but significant weight gain,
sizeable increases in visceral fat. The weight and visceral fat
gain was accompanied by additional metabolic deterioration
within 6 months of continued inactivity. In Table 1, we show
12 health-related variables that were observed to worsen sig-
nificantly (P < 0.05) in the inactive control group.
Hamilton  et  al. have addressed the problem of inactivity
from a somewhat different perspective. In an important paper
(16), they present a compelling and well-developed case that
society has not reached the pinnacle of non-exercise-related
physical inactivity and inactivity-related morbidity and mortal-
ity. Specifically, they suggest that individuals, who are already
nonexercisers and are not physically active, can reduce total
activity even further. Their case is based on the well-grounded
assumption that individuals who do not currently exercise
can still become even more inactive due to expected contin-
ued technological advances that almost certainly will lead to
increases in daily sitting time.
Exercise, Body Weight, and Composition—Evidence
of a Dose–Response Relation
It is clear that decreases in physical activity play an impor-
tant role, perhaps even a dominant role (24–26), in the rapid
increases in obesity prevalence over the past few decades.
However, the amount of activity needed to prevent weight
gain is not known. Although previously controversial, it is
now evident from numerous studies that moderate amounts
of regular exercise can and does lead to moderate weight loss
and even more significant fat mass loss when undertaken by
previously sedentary individuals (27–29). Exercise studies
have typically been conducted on lean individuals, or if they
were with ­overweight/obese individuals; the exercise stimulus
in terms of total weekly caloric expenditure was often quite
small. This led to the mistaken perception that regular exer-
cise will only result in modest weight loss. In a classic study of
exercise-only vs. diet-only interventions, Ross et al. (18) com-
pared an exercise stimulus (700 kcal expended per day, 7 days
a week for 14 weeks) that was, for the first time, equivalent
Table 1 Effects of 6 months of continued physical inactivity
in sedentary individuals
↑ Body weight ↑ Total abdominal fat ↑ LDL particle #
↑ Waist circumference ↑ Fasting insulin ↑ Small dense LDL
↑ Waist-to-hip ratio ↓ Insulin sensitivity ↓ LDL size
↑ Visceral fat amount ↓ Fitness (TTE) ↑ LDL-cholesterol
Results above were taken from previously published results from STRRIDE
(6,11,12,29,45).
S28 VOLUME 17 SUPPLEMENT 3 | DECEMBER 2009 | www.obesityjournal.org
to the diet intervention (reduced caloric intake of 700 kcal per
day for 14 weeks). This was important because the typical diet
vs. exercise comparison generally involves a substantial caloric
deficit through diet vs. a very modest exercise intervention and
as a result, diet is generally considered the only way to lose
weight. In this study in men, both interventions reduced body
mass by 7.5 kg (~8%). In another study of similar design, this
time in women (this time 500 kcal/day change in caloric bal-
ance with diet vs. exercise), Ross et al. (30) reported a weight
loss of ~6.5%. These data show that weight loss is similar when
the same degree of negative energy balance is produced by diet
alone compared with exercise alone.
In a 2001 review, Ross and Janssen (31) presented data iden-
tifying a dose–response relationship between exercise amount
and reductions in both fat mass and body weight loss. That is,
when sedentary individuals begin a regular exercise program,
they lose weight, and the more exercise they do, the greater
the weight and fat mass loss. At the time of this 2001 review,
no randomized, controlled studies had been conducted that
actually directly tested the effects of two different amounts of
exercise vs. a control group. Although STRRIDE was designed
to investigate the effects of the different amounts and intensi-
ties of exercise on cardiovascular risk factors in middle-aged,
overweight and mildly obese men and women with mild-to-
­moderate dyslipidemia (32), this design also allowed us to
study the effects of these three different exercise interventions
on several markers of body habitus. Briefly, out of 387 subjects
recruited, 260 subjects completed the randomized, control-
led trial of the effects of either a control group or one of three
different exercise-training interventions: (i) low-amount/
moderate-intensity group; the actual exercise prescription was
to do 14 kcal/kg body weight/week of exercise at 50% peak
VO2, equivalent to walking 12 miles/week; (ii) low-amount/
vigorous-intensity group; the actual exercise prescription was
14 kcal/kg/week of exercise at 75% peak VO2, equivalent to
jogging 12 miles/week; (iii) high-amount/vigorous-intensity
group; the actual prescription was to do 23 kcal/kg/week at
75% peak VO2, which was equivalent to jogging 20 miles/week.
This design allowed us to compare groups 1 and 2 to deter-
mine whether there was an exercise intensity effect and groups
2 and 3 to determine whether there was a dose–response effect,
i.e., whether more exercise was better.
With regard to body weight, we found that even without
changes in diet, 73% of our overweight or mildly obese sub-
jects were able to prevent weight gain or experience modest
weight loss with 180 min of moderate-intensity exercise each
week (29). Moderate amounts of exercise also led to significant
loss of total body fat mass (Figure 1). More activity (the high-
amount group) resulted in greater weight loss, fat loss, and
reductions in measures of central obesity (Figure 1). There was
no significant effect of exercise intensity as the low-amount of
vigorous exercise led to approximately the same weight loss
and fat mass loss as an equal amount of moderate-intensity
exercise (group 1 vs. 2). This study along with the studies by
Ross et al., clearly showed that a calorie is a calorie—whether
a moderate- or vigorous-intensity exercise calorie or whether

a 2
0
0 4 8 12 16 20
−2
−4
b 2
0
0 4 8 12 16 20
−2
−4
−6
c 12
6
0 2 diabetes is well established. Visceral fat compared to total
0 4 8 12 16 20
−6
Exercise equivalent (miles/week)
−12
Figure 1  Relationship between amount of exercise per week and
(a) body weight change, (b) fat mass change, and (c) visceral fat
change. Figure adapted from data from Slentz et al. (37).
a diet vs. exercise calorie. When taken together, these studies
indicate that, with regard to exercise, weight change is all about
the degree of caloric imbalance created through the exercise
program (with moderate or vigorous intensity), and impor-
tantly, that exercise can be as effective as diet for weight loss.
Total and NonExercise Physical
Activity Energy Expenditure
No discussion of the effects of exercise on body weight would
be  complete with discussing whether an exercise program
leads to a compensatory reduction in other physical activity.
Although it is widely assumed that incorporating an exer-
cise program into one’s daily routine will increase overall
physical activity, the literature on this issue is not conclusive.
Meijer  et  al. (33) and Goran  et  al. (34) demonstrated that
total daily energy expenditure in “elderly” subjects (aver-
age age 58 years and 66 years, respectively) was unchanged
at the end of 12- and 8-week training programs, concluding
that reductions in nonexercise physical activity compensate
for exertion during exercise sessions. However, in a study by
Meijer et al., younger subjects preparing for a half marathon
demonstrated an increase in total physical activity energy
expenditure (PAEE), but with no significant change in nonex-
ercise physical activity, i.e., no compensation in other activity
(35). This may suggest that although younger individuals may
not compensate, perhaps middle-aged and older individuals
do. However, we recently reported (36), from the STRRIDE
study on subjects who were 40–65 years of age, that there was
a clear increase in total PAEE/h with no evidence of compen-
sation by reducing other physical activities—in fact there was
obesity | VOLUME 17 SUPPLEMENT 3 | DECEMBER 2009 S29
articles
a tendency for nonexercise physical activity to increase too
(albeit not quite significant). This is certainly consistent with
the observed decreases in body mass and fat mass in all three
exercise groups, which could not occur if increased exercise
expenditure was compensated for by reductions in other
physical activity (37). We believe that the 8-month duration
of our exercise-training program principally differentiates it
from those that demonstrated no change in total PAEE. This
longer training program is much more likely to replicate the
chronic effects of regular exercise than a program of a few
months or less. We hypothesize that the effect of an exercise
program on total and nonexercise PAEE depend on the dura-
tion of that program.
Effects of Exercise on Visceral Fat
The unique importance of visceral fat and its consistent asso-
ciations with risk factors for coronary heart disease and type
body fat is a significantly better correlate with triglycerides,
systolic and diastolic blood pressure, high-density lipoprotein
(HDL)/total cholesterol ratio and area under the insulin curve
in response to a glucose challenge. Visceral fat has been shown
to explain approximately twice the amount of variance in these
variables when compared to total body fat (38,39). Comparing
lean insulin-sensitive subjects to lean insulin-resistant subjects
and to obese insulin-resistant subjects, Despres et al. data show
that differences in visceral fat explain much of the atherogenic
lipoprotein profile that is associated with obesity and insulin
resistance (40). However, whether visceral obesity is causally
related to disease or simply associated is controversial (41,42).
Either way, the consistent, significant associations between vis-
ceral adipose tissue (VAT) and risk factors for coronary heart
disease and type 2 diabetes indicate that it is a good marker of
increased risk for these diseases.
There are a number of excellent, well-designed studies that
have studied the effects of exercise on VAT. In a 12-week study
in overweight men, Ross et al. (18) reported that an exercise
program designed to increase energy expenditure by 700 kcal/
day for 12 weeks resulted in a weight loss of 7.5 kg and a decrease
in VAT of 52 cm2 (reported as the cross-sectional area of fat on
a single-slide computed tomography scan), corresponding to
a decrease of 6.9 cm2 VAT fat per kilogram of weight loss. The
men in their diet-only group (700 kcal deficit) had a smaller
but similar decrease of 5.9 cm2 per kilogram of weight loss. In
STRRIDE, the men in the high-amount exercise group experi-
enced a reduction of 5.6 cm2/kg of weight loss (6). Irwin et al.
(43) studied the effects of a 12-month exercise program in
overweight postmenopausal women. In this study, they used
a significant exercise exposure consisting of at least 45 min of
moderate-intensity exercise, 5 days/week for 12 months. They
reported a loss of 8.5 cm2 of VAT and 1.3 kg of body weight,
corresponding to a ratio of 6.5 cm2/kg of weight change. In the
high-amount exercise group from STRRIDE, the women lost
6.9 cm2 of VAT per kilogram of body weight (6).
Although it is clear that sufficient exercise can lead to reduc-
tions in VAT, at the time of the 2001 review, Ross and Janssen
articles

concluded that there were insufficient data to determine
whether there is a dose–response relationship between exer-
cise amount and changes in VAT. Data from STRRIDE revealed
that the middle-aged men and women in the inactive control
group appeared to fairly aggressively increase visceral fat dur-
ing the control period, whereas both of the low-amount exer-
cise groups prevented this increase (with no apparent effect of
exercise intensity) and the high-amount group led to significant
and sizeable decreases in VAT (Figure 1). These data confirm
that there is a dose–response relation between amount of exer-
cise and changes in visceral fat. A 2008 review found that there
is now adequate data to conclude that there is a dose–response
relationship between VAT change and ­exercise amount.
Does exercise lead to preferential reductions in visceral fat
over abdominal subcutaneous fat and/or does exercise lead to
a preferential reduction in central vs. peripheral fat? This is a
controversial question as some studies have shown a preferen-
tial reduction in central vs. peripheral fat (27,44). However, we
did not observe a preferential reduction of central fat in any of
the three exercise groups (37). Instead, all three groups expe-
rienced similar percent reductions in both central and periph-
Where Moderate-Intensity May be Better
than Vigorous-Intensity Exercise
Interestingly, three important diabetes risk–related variables
were improved more by moderate-intensity than vigorous-
­intensity exercise. Moderate-intensity exercise was significantly
more effective at lowering triglycerides (TGs) (12) and improv-
ing insulin sensitivity index (45) than was vigorous exercise
(see Figure 3, in ref. 46). These patterns (moderate-intensity
better than vigorous) were observed for both men and women
(data not shown). Also, metabolic syndrome score improved
significantly with low-amount/moderate, but did not with
low-amount/vigorous-intensity exercise (12) (see Figure 3).
Finally, in part of the STRRIDE study that was designed to
separate the acute from the sustained effects of exercise, it was
of interest that moderate-intensity but not vigorous-intensity
exercise resulted in sustained TG lowering (12). Only the low-
amount/moderate-intensity group experienced significantly
a 200
100

eral skinfolds. Neither did we observe a significant change in

waist-to-hip ratio in any exercise group. Interestingly, we did 0
0 4 8 12 16 20
see that in the inactive control group there was a preferential
−100
deposition of fat in the central vs. peripheral depot as indicated
by a significant increase in the waist-to-hip ratio. b 0.4

0.2
How Much Exercise is Enough
0.0
for Health Benefits? 0 4 8 12 16 20
The answer depends on both the variable of interest and the −0.2

population being studied. Exercise physiologists and health −0.4

professionals have long suspected that the amount of exercise
needed would very likely depend on the health-related vari- c 0.2

able in question. Our experience from STRRIDE would sup-

0.1
port this notion. In Figures 1 and 2, we present the STRRIDE
data represented another way (i.e., here, the data are plotted by 0
exercise amount instead of by group—see Figure 3 for example 0 4 8 12 16 20

of data plotted by group) to represent the relationship between −0.1

Exercise amount (miles/week)

exercise amount and body habitus changes in Figure 1, and

changes in lipoprotein variables (lipoprotein particle size and
number) the data from the figures of HDL and LDL size above)
in Figure 2. In each of the three graphs to the left, the curve
crosses the x-axis at different places. The point where the graph
crosses the x-axis suggests how much exercise is needed just
to prevent the deterioration seen with continued sedentary
Figure 2  Relationship between amount of exercise per week and
(a) low-density lipoprotein (LDL) particle number change, (b) LDL
size change, and (c) high-density lipoprotein (HDL) size change.
Data from Kraus et al. (11). Figure reprinted with permission from
Slentz et al. (60).
Metabolic syndrome score change

0.5 versus control

living—i.e., the “break-even” point—and that above this point, 0
P < 0.02 NSD P < 0.0001
improvements begin to accrue. For both visceral fat (Figure 1c)
−0.5
and LDL particle change (Figure 2a), the graphs would sug-
gest that to decrease VAT or the LDL particle number would −1
P = 0.07 P = 0.001
require approximately >13 miles of exercise per week. However, −1.5
versus high amount group
changes in fat mass (Figure 1b) and the size of the LDL par-
−2
ticles (Figure 2b) were more responsive to exercise, with the Control Low-amount/ Low-amount/ High-amount/
data suggesting that amounts >4 miles (for fat mass) or 7 miles/ moderate intensity vigorous intensity vigorous intensity

week (for LDL size) would start to return benefits. The amount Figure 3  Effect of exercise amount and intensity on metabolic syndrome
of exercise needed to lose weight (>8 miles/week) or increase score. Figure reprinted from Johnson et al. (12) with permission from
HDL size (>10 miles/week) fell somewhere in the middle. Elsevier. NSD, no significant difference.

S30 VOLUME 17 SUPPLEMENT 3 | DECEMBER 2009 | www.obesityjournal.org


lower TGs after 5 and 14 days of no exercise. Both vigorous
exercise groups returned to baseline soon after exercise train-
ing stopped. Although the mechanism(s) are yet not clear, it
seems likely that either lipoprotein lipase activity was increased
more (resulting in increased TG clearance) or that overall liver
very low–density lipoprotein production was reduced more by
moderate-intensity exercise.
Is Exercise Amount or Exercise Intensity
More Important?
Although the above findings suggest that moderate-inten-
sity exercise may be more effective than vigorous-intensity
exercise for some health-related variables, it is impor-
tant to remember that even for these variables there was a
dose–response relationship between amount of exercise
and magnitude of the benefit (albeit for vigorous intensity
only, as STRRIDE was not designed to study dose response
for moderate-intensity exercise). The major and most con-
sistent findings from STRRIDE was that a modest amount
of exercise (vigorous or moderate intensity) was better than
no-exercise and that the largest and most widespread benefits
were observed in the group that did the most exercise. In lay-
man’s terms, the most important message is that for health
benefits in sedentary individuals, some exercise is better than
none, and more is better than less. It is clear that the majority
of research supports this concept as this is one of the major
messages from the 2008 Physical Activity Guidelines for
Americans from the United States Department of Health and
Human Services (47).
Skeletal Muscle Fatty Acid Oxidative Capacity,
Insulin Resistance, and Body Mass Homeostasis
Skeletal muscle is a metabolically active tissue that is critical to
maintaining whole-body homeostasis and plays an important
role in FAO. At rest, the oxidation of lipid contributes signifi-
cantly to overall energy needs with most of the energy require-
ments of muscle being obtained via FAO, which is quantitatively
important due to muscle mass. Factors that elicit a decrement
in the ability to oxidize lipid in skeletal muscle would thus be
anticipated to evoke profound changes in whole-body lipid
and fat mass homeostasis.
There are limited prospective data indicating that a propen-
sity for weight gain is associated with a low rate of lipid oxi-
dation in skeletal muscle. In Pima Indians, Zurlo et al. (48)
reported that a low capacity for fat oxidation, as measured
with whole-body indirect calorimetry, was associated with an
increased risk for weight gain. Similar findings were obtained
by Marra  et  al. (49) who observed that weight gain in lean
women was associated with a low rate of whole-body fat oxi-
dation. Other work has supported the premise that a low rate
of fat oxidation is predictive of weight gain in both lean and
obese individuals (50).
Studies examining the effect of weight loss on substrate
utilization in obese individuals have obtained similar results.
Larson  et  al. (51) studied previously obese individuals who
lost a mean of 57 kg via energy restriction and found that fat
obesity | VOLUME 17 SUPPLEMENT 3 | DECEMBER 2009 S31
articles
oxidation (as determined with indirect calorimetry) was sig-
nificantly depressed in the weight-loss (postobese) group
compared to weight-matched controls. Similarly, Kelley et al.
(52) reported no change in the capacity for fat oxidation when
determining substrate utilization across a skeletal muscle bed
of obese individuals before and after weight loss. In postobese
individuals, there is a decrement in fat oxidation during sub-
maximal exercise as well as at rest (for review see ref. 53) and
in extremely obese individuals, which persists after weight loss
of ~100 kg (refs. 45,54–56). Measurements in skeletal muscle
indicate a loss in lipid oxidative capacity in obese individuals,
particularly extremely obese subjects (54,56).
Insulin resistance is a health concern in the obese. The coex-
istence of insulin resistance and a decrement in FAO in skele-
tal muscle sometimes coexist in obese individuals (for reviews
see refs. 53,57). However, the mechanistic link between FAO
and insulin resistance in the skeletal muscle of obese indi-
viduals does not yet exist. There is evidence suggesting that
the accumulation of lipid within the skeletal muscle of obese
individuals induces insulin resistance. Some work suggests
that metabolites such as long-chain acyl CoA, diacylglycerol,
and ceramide accumulate in the cytosol of the skeletal muscle
of obese individuals. These intermediates then either directly
or indirectly impair insulin signal transduction and/or the
activity of enzymes involved in glucose utilization, which in
turn induces insulin resistance (for review see ref. 58). The
accumulation of these metabolically active lipid intermediates
could be due, at least in part, to the disturbances in mitochon-
drial function the ability to completely oxidize fatty acids to
acetyl-CoA. The accumulation of incompletely oxidized fatty
acid metabolites, such as ceramide, interfere with insulin sig-
naling and lead to insulin resistance (59).
In summary, it is evident that exercise in sufficient amounts
can lead to substantial decreases in body weight, total body
fat, and visceral fat. Additionally, evidence now supports the
conclusion that there is a dose–response relationship between
exercise amount and body weight, body fat, and visceral fat—
i.e., that more exercise leads to additional benefits. There are
a number of important cardiometabolic risk factors that were
most favorably effected by moderate intensity compared to
vigorous-intensity exercise. Additional research will be neces-
sary to confirm these findings. Unfortunately, it is also appar-
ent that in sedentary middle-aged men and women, relatively
short periods of physical inactivity lead to significant weight
gain, substantial increases in visceral fat, and further meta-
bolic deterioration. Finally, exercise training–induced changes
in mitochondrial oxidative capacity in skeletal muscle appear
to improve insulin action by reducing the accumulation of
incompletely oxidized fatty acids.
Acknowledgments
This work was supported by National Institute of Health grant HL-57354.
Disclosure
C.A.S. has declared no financial interests. J.A.H. has received grant support
from Children’s Research Institute. W.E.K. has declared no financial
interests.
© 2009 The Obesity Society
articles
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