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Exercise and Diet, Independent of Weight

Loss, Improve Cardiometabolic Risk Profile in
Overweight and Obese Individuals

Glenn A. Gaesser PhD, Siddhartha S. Angadi BOTh & Brandon J. Sawyer MEd

To cite this article: Glenn A. Gaesser PhD, Siddhartha S. Angadi BOTh & Brandon J. Sawyer
MEd (2011) Exercise and Diet, Independent of Weight Loss, Improve Cardiometabolic Risk
Profile in Overweight and Obese Individuals, The Physician and Sportsmedicine, 39:2, 87-97

To link to this article: http://dx.doi.org/10.3810/psm.2011.05.1898

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Exercise and Diet, Independent of Weight Loss,
Improve Cardiometabolic Risk Profile in
Overweight and Obese Individuals
Glenn A. Gaesser, PhD 1
Siddhartha S. Angadi, BOTh 1
Downloaded by [University of Cambridge] at 13:53 05 November 2015
Brandon J. Sawyer, MEd 1
1
Healthy Lifestyles Research Center,
College of Nursing and Health
Innovation, Arizona State University,
Mesa, AZ
Correspondence: Glenn A. Gaesser, PhD,
Healthy Lifestyles Research Center,
Arizona State University,
7350 E. Unity Ave.,
Mesa, AZ 85212.
Tel: 480-727-1944
Fax: 480-727-1051
E-mail: glenn.gaesser@asu.edu
© The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847
CLINICAL FOCUS: DIABETES AND OBESITY
Abstract
Diet and/or exercise are routinely advised as methods for weight loss in overweight/obese indi-
viduals, particularly those who are at high risk for cardiovascular disease and type 2 diabetes
mellitus. However, physical activity and structured exercise programs rarely result in significant
loss of body weight or body fat, and weight-loss diets have extraordinarily high recidivism rates.
Despite only modest effects on body weight, exercise and ad libitum nutrient-dense diets for
overweight/obese individuals have many health benefits, including skeletal muscle adaptations
that improve fat and glucose metabolism, and insulin action; enhance endothelial function; have
favorable changes in blood lipids, lipoproteins, and hemostatic factors; and reduce blood pres-
sure, postprandial lipemia and glycemia, and proinflammatory markers. These lifestyle-induced
adaptations occur independently of changes in body weight or body fat. Thus, overweight/obese
men and women who are at increased risk for cardiovascular disease and type 2 diabetes as a
result of sedentary lifestyle, poor diet, and excess body weight should be encouraged to engage
in regular physical activity and improve their diet, regardless of whether the healthier lifestyle
leads to weight loss.
Keywords: exercise; physical activity; diet; lifestyle; obesity; diabetes
Introduction
Weight loss has been the primary treatment goal for individuals who are overweight
or obese, particularly those with type 2 diabetes mellitus and/or cardiovascular
comorbidities. A weight loss of approximately 10% of initial body weight has been
recommended as an initial target goal.1,2 This goal is often difficult to achieve through
lifestyle interventions,3 and studies of long-term weight-loss maintenance indicate high
recidivism rates.4 Because the prevalence of weight-loss attempts among US adults
is so high (46% for women; 33% for men),5 this sets the stage for a pattern of chronic
weight fluctuation that may be harmful.6–8
Consequently, lifestyle interventions have been advocated that focus more on
behavior (eg, exercise and diet) than weight loss.9–11 There is considerable support for
a non–weight loss-centered paradigm, which shows that many obesity-related health
conditions can be substantially improved through changes in exercise and diet and
are independent of weight loss (Table 1). This paradigm also predicts that increasing
physical activity and improving the quality of a diet should have a far more beneficial
impact on premature mortality than weight loss.10 In establishing an evidence-based
approach for this paradigm, we fully acknowledge the documented benefits of weight
loss in obese, at-risk populations.1,2,12–19 However, because individuals who lose weight
87
 Gaesser et al

tend to gain it back,4 alternative approaches to treatment This article briefly describes the relevant research that
of excess body weight and associated comorbidities are shows that in overweight/obese individuals, either with
warranted. (or who are at risk for) type 2 diabetes and/or cardiovas-
cular disease (CVD), cardiometabolic risk markers can
Table 1. Health Benefits of Exercise and/or Diet for Overweight be improved, if not entirely ameliorated, through lifestyle
and Obese Individuals, Independent of Changes in Body Weight intervention, independent of weight loss. This non–weight
or Body Fat loss-centered approach may provide physicians with a strong
Glucose metabolism and insulin action
rationale for prescribing exercise and a healthier diet to
Decreased fasting glucosea
Decreased fasting insulinb
overweight/obese patients, for whom sustained weight loss
Increased glucose tolerancec has often proved unattainable.
Increased insulin sensitivityd
Decreased HbA1ce Reduction in Type 2 Diabetes Risk
Blood pressure
Lifestyle interventions that include weight loss as a goal have
Decreased resting systolic blood pressuref
Decreased resting diastolic blood pressureg been reported to reduce incidence of type 2 diabetes.15–19 In
Decreased ambulatory blood pressure30,55,56 both the Diabetes Prevention Program (DPP) and Finnish
Downloaded by [University of Cambridge] at 13:53 05 November 2015

Lipids and lipoproteins Diabetes Prevention Study (FDPS), mean weight loss after 3
Decreased cholesterolh
to 4 years of intervention averaged approximately 3 to 4 kg,
Decreased LDL-C or oxidized LDLi
Increased HDL-Cj
and type 2 diabetes risk was reduced by 58%.15,16 Subsequent
Decreased triglyceridesk analyses indicated that weight loss was the dominant
Improved lipid subfractions33,61,64n,98 predictor of reduced type 2 diabetes incidence in both of these
Endothelial function interventions.18,19 However, weight loss may not be necessary
Increased vascular dilatory functionl
to reduce the incidence of type 2 diabetes.
Hemostasis
Increased tissue plasminogen activator release capacity83 Two more recent lifestyle intervention programs revealed
Fibrinolytic control83 significant reductions in type 2 diabetes incidence with either
Decreased fibrinogen28 no weight loss20 or only minor weight loss (1.08 kg).21 In the
Decreased plasminogen activator inhibitor-134n PREDIMED trial, a Mediterranean diet was supplemented
Decreased MMPs28,82
with either virgin olive oil or nuts. Over a 4-year period, type
Increased MMP inhibitors (tissue factor pathway inhibitors)28
Tissue factor pathway inhibitor57n 2 diabetes incidence was reduced by 52% compared with a
Inflammation control, low-fat diet group.20 Similarly, in the 3-year Study
Increased anti-inflammatory markers29,44 of Lifestyle Intervention and Impaired Glucose Tolerance
Decreased proinflammatory markersm
Maastricht (SLIM),21 the lifestyle intervention group expe-
Skeletal muscle adaptations
Mitochondrial enzyme increase in number and activation22,39,42,94
rienced a 58% reduction in type 2 diabetes incidence despite
Increased mitochondrial fat oxidation22,39,42,94 a mean weight loss of only 1.08 kg. These reductions in type
Decreased muscle diacylglycerol content22 2 diabetes incidence are comparable with those observed in
Decreased muscle ceramide content22 the DPP and FDPS, yet weight loss was either much less or
Postprandial metabolism
entirely absent. Thus, lifestyle interventions may be effective
Decreased lipemia43,97,98
Decreased glycemia24,43 in reducing type 2 diabetes in at-risk populations, even when
a
References 24,28–30,31n,32n,33,34n,35,36n
body weight remains largely unchanged. We contend that
b
References 22–24,26,27,29,30,32n,37–39 reductions in type 2 diabetes risk, in the absence of weight
c
References 22–27
d
References 22,23,25–27,29,30,31n,32n,36n,37,38,40–43 loss, are largely due to the beneficial effects of exercise and/
e
References 24,28,29,33,44,45
f
References 24,29,30,31n,36n,44o,54,56,57–59n,60o,101 or improved diet on glucose metabolism and insulin action,
g
References 24,28,30,31n,36n,44o,54,56,58n,59n,60n,76n
h
References 28,29,31n,32n,33,44o,60o,64n,65n,67o
independent of weight loss.
i
References 27–29,31n,34n,60o,65n,66n,67o
j
References 24,29,30,31n,32n,36n,44,60o,62,89
k
References 24,27,29,30,31n,32n,33,60o,61,62,64n,67o,89,97,98 Glucose Metabolism and Insulin
l
References 63,72–75,76–78n,99
m
References 31n,32n,35,36n,44,82,89,90,91–93n,98 Action
n
Diet intervention
o
Exercise and diet intervention.
Aerobic exercise training, independent of changes in body
Abbreviations: HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein weight, has been shown to significantly increase glucose
cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein
cholesterol; MMPs, matrix metalloproteinases. tolerance,22–27 reduce fasting and postprandial glucose,24,28–36

88 © The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847

reduce fasting insulin,22–24,26,27,29,30,32,37–39 enhance insulin sen-
sitivity,22,23,25–27,29–32,36–38,40–43 and reduce glycated hemoglobin
(HbA1c)24,28,29,33,44,45 in overweight and obese individuals. In
these studies, anthropometric indices were either unchanged
or decreased minimally (eg,  2%), suggesting that loss of
body fat was not a major factor in the adaptation. In fact,
exercise training may enhance insulin sensitivity even when
increasing adiposity after training.38 These findings may be
partly explained by the fact that just 1 bout of exercise can
improve insulin sensitivity,40,46 and that this effect may persist
for up to 72 hours after exercise.40
It is well established that weight loss significantly
improves glucose metabolism and insulin action in overweight
and obese individuals.47–51 However, metabolic improvements
associated with weight loss may be reversed during weight
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regain.52 In an observational study of obese men and women,
improvement in insulin action and insulin secretion associated
with a 10% weight loss was entirely reversed during weight
regain.52 Because significant weight loss (∼10%) is difficult to
maintain,3 the documented benefits of significant weight loss
in risk management may be transient. Furthermore, instabil-
ity of metabolic risk factor levels, such as insulin resistance
(which can occur because of chronic weight fluctuation), has
been reported to significantly predict atherosclerotic vascular
disease during an 11.6-year period.6
For improving HbA1c, exercise training resulting in small
to no amounts of weight loss appears to be just as effective
as significant weight loss through calorie restriction. For
example, a weight loss of 8 to 10 kg (8.6%) after 1 year
in the Look AHEAD trial reduced HbA1c by 0.64%.47 In
contrast, in a meta-analysis of 27 exercise training studies
(5–52 weeks in duration) involving individuals with type
2 diabetes, it was revealed that exercise training decreased
HbA1c by approximately 0.8%.24 The authors noted that
this effect is similar to that observed with dietary, drug,
and insulin treatments. Weight loss appeared to have little
effect on the improvement in glycemic control because the
improvement in HbA1c with aerobic exercise training alone
(−0.7%) was about the same as that observed for combined
aerobic and resistance exercise training (−0.8%), even
though weight loss was much greater for the combined
training (−5.1%) than for aerobic exercise training alone
(−1.5%). A large randomized clinical trial of 251 adults with
type 2 diabetes demonstrated that both aerobic and resistance
training reduced HbA1c by 0.4% to 0.5%, but improvements
were greatest for combined aerobic and resistance train-
ing (0.9%).45 Although combined training reduced HbA1c
by twice as much as either mode alone, changes in body
© The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847
Weight Loss-Independent Effects of Exercise and Diet
weight (2.6 kg) and fat mass (1.6–1.9 kg) were the same
for all groups.
Both aerobic and resistance exercise training are effec-
tive for improving insulin sensitivity. Six months of either
aerobic or resistance training in overweight/obese men
increased glucose disposal by 20% to 25%, as assessed
by a glycemic-hyperinsulinemic clamp.41 It is unlikely
that reduced fat mass played a role because total fat mass
remained unchanged after resistance training (+0.7 kg), yet
was significantly reduced after aerobic exercise training
(−2.1 kg). It has been suggested that changes in visceral
adipose tissue that occur as a result of exercise training are
responsible for the changes in insulin sensitivity.27 However,
improvements in insulin sensitivity occur in the absence of
reductions in visceral adipose tissue.41 In overweight/obese
men and women who participated in the Studies of Targeted
Risk Reduction Interventions Through Defined Exercise
(STRRIDE), equal improvements in insulin sensitivity
were achieved for both moderate- and vigorous-intensity
programs despite greater reductions in visceral adipose tis-
sue after the vigorous-intensity program.53
Dietary interventions that focus on improving diet
quality also improve glucose metabolism and insulin action
in the absence of clinically significant weight loss.31,32 In a
12-week dietary intervention in adults with type 2 diabetes or
impaired fasting glucose, in which refined rice was replaced
with whole grains and vegetable intake was increased, sig-
nificant improvements in fasting glucose and Homeostasis
Model of Assessment–Insulin Resistance (HOMA-IR) were
observed, despite body mass index (BMI) decreasing by just
0.2 units.31 In a 3-month study of overweight/obese men and
women at risk for CVD, it was demonstrated that when the
participants consumed a Mediterranean diet for 3 months,
fasting glucose and insulin were reduced and insulin sensitiv-
ity was improved, despite no statistically significant changes
in body weight or weight circumference.32 After 4 years of
follow-up, the Mediterranean diet reduced incidence of type
2 diabetes by 52%, despite no reduction in body weight.20
Blood Pressure
Both aerobic and resistance exercise training have been
shown to reduce resting and ambulatory blood pressure, with
blood pressure improvements often occurring independently
of weight loss.24,28–30,54–56 In a 6-week program in which
168 overweight men and women with stage I hypertension
participated in brisk walking, 24-hour ambulatory systolic
and diastolic blood pressures were reduced (systolic, from
143.1 to 135.5 mm Hg; diastolic, from 91.1 to 84.8 mm Hg)
89
 Gaesser et al
without reducing body weight.55 A meta-analysis of 72
exercise intervention trials found that training reduced
resting and ambulatory blood pressure in normotensives
by approximately 3 to 4 mm Hg and in individuals with
hypertension by approximately 5 to 7 mm Hg.30 These
improvements occurred despite minimal changes in body
weight (∼1.2 kg) and percent body fat (∼1.4%). Correlations
between changes in BMI, systolic blood pressure (r = 0.09),
and diastolic blood pressure (r = 0.07) are extremely low,54
suggesting that decreases in BMI explain  1% of the
changes in blood pressure with exercise training. Resistance
exercise also lowers blood pressure in overweight and obese
individuals. In a meta-analysis by Kelley,56 it was demon-
strated that resistance training in both normotensive and
hypertensive individuals resulted in a 3% to 4% reduction in
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blood pressure with no significant changes in body weight.
Improvements in the quality of diet can lower blood
pressure without any significant weight loss.32,36,57–59 This
is best exemplified by the Dietary Approaches to Stop
Hypertension (DASH) trial.58 Specifically designed to
assess the impact of diet on blood pressure in the absence of
weight loss, the DASH diet reduced both systolic (−5.5 mm
Hg) and diastolic (−3.0 mm Hg) blood pressure. Among
133 men and women with hypertension, consuming more
fruits and vegetables, as well as dairy foods low in saturated
fat, was sufficient to reduce systolic blood pressure by an
average of 11.4 mm Hg, and diastolic blood pressure by an
average of 5.5 mm Hg in a 2-week period.58 The reductions
in blood pressure were comparable with those observed with
administration of pharmacotherapy. More significantly, the
reductions in blood pressure were achieved without any
weight loss. The DASH diet is associated with an increased
intake of potassium and magnesium, and these have been
linked to reduced blood pressure. In a recent study, however,
supplementing patients’ usual diets, which are usually low
in fruits and vegetables, with diets rich in potassium and
magnesium to match those of the DASH diet, did not lower
blood pressure by as much as the DASH diet alone, suggest-
ing that the blood pressure-lowering effect of the DASH diet
extends beyond any impact attributable to potassium and
magnesium.59 Even when weight loss occurs with exercise
and/or noncalorically restricted dietary interventions that
lower blood pressure, the amount of weight loss is modest
and correlates weakly, if at all, with the magnitude of blood
pressure reduction.60 In a combined exercise and diet inter-
vention, results showed an 18.8-mm Hg decrease in systolic
blood pressure and an 8.0-mm Hg decrease in diastolic
blood pressure.60 Weight loss was modest (4 kg; 3.7%) and
90 © The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847
was not associated with the magnitude of blood pressure
reduction.
For comparison, in the Look AHEAD trial of intentional
weight loss, an 8.6% reduction in body weight reduced
systolic blood pressure by 6.8 mm Hg and diastolic blood
pressure by 2.9 mm Hg.47 In a meta-analysis of weight loss
interventions in patients with type 2 diabetes, a weight loss
of 9.6% (9.2 kg) was associated with decreases of 8.1%
(∼11 mm Hg) and 8.6% (∼7 mm Hg) for systolic and diastolic
blood pressure, respectively.12
Lipids and Lipoproteins
Exercise training appears to have diverse, somewhat
inconsistent effects on serum levels of lipids and may vary
by modality. In general, however, it has favorable effects
on lipids and lipoproteins, even in the face of unchanged
body weight24,28–30,33,44 or clinically insignificant weight loss
( 2%).53,61 A meta-analysis of 27 studies concluded that
aerobic exercise was associated with a small but statistically
significant effect on increasing high-density lipoprotein
cholesterol (HDL-C) levels and exhibited a trend toward
decreasing serum triglyceride levels.24 Another meta-analysis
of 72 studies indicated a small but statistically significant
effect of aerobic exercise on increasing HDL-C, and a trend
(P = 0.07) for a reduction in triglycerides; overall changes
in body mass (∼1.2 kg) and body fat ( 2.0%) were small.30
In 1 study of Asian Indians with type 2 diabetes, Misra et al33
reported that 12 weeks of resistance exercise training reduced
total cholesterol (8.5%), triglycerides (19.6%), and very
low-density lipoprotein cholesterol (LDL-C) (32.1%), with
no changes in BMI or total body fat. In a randomized trial
carried out on overweight, sedentary, and dyslipidemic men
and women, 8 months of exercise training (varying in amount
and intensity) improved 11 different lipid and lipoprotein
variables in the absence of clinically significant weight loss
( 1.52 kg).61
Aerobic exercise may be of particular value in treating
individuals with the most atherogenic lipids profiles. In
1 study, 20 weeks of aerobic exercise training was more
effective at improving lipid and lipoprotein profiles in
overweight men with a combination of low HDL-C and
elevated triglycerides than in men with either isolated low
HDL-C or elevated triglycerides.62 High-density lipoprotein
cholesterol was increased by 4.9% and triglycerides were
reduced by 15%, despite small changes in weight (−0.7 kg)
and fat mass (−1.1 kg). Similarly, in both overweight/obese
adults with and without type 2 diabetes, an 8-week program
of aerobic exercise significantly reduced total cholesterol

(8%–13%) and LDL-C (13%–19%), and increased HDL-C/
total cholesterol (10%–17%), but did not significantly alter
body weight or fat mass.63
A number of dietary interventions show that lipid profile
can be improved independently of weight loss.31,32,64–66 In
patients with type 2 diabetes, Chandalia et al64 reported that
the addition of 26 g per day of soluble and insoluble fiber to
the American Diabetes Association diet for 6 weeks reduced
total cholesterol (−14 mg/dL), triglycerides (−21 mg/dL), and
very LDL-C (−5 mg/dL) without demonstrating any changes
in body weight. Chung et al31 also demonstrated that replac-
ing refined rice with whole grains and increasing vegetable
intake for 12 weeks reduced triglycerides, total cholesterol,
and LDL-C, and increased HDL-C in patients with type 2
diabetes, though only a modest (0.4 kg) decrease in body
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weight was achieved.
Combined diet and exercise interventions may be supe-
rior to either exercise or diet alone.60,67 Among 4587 men
and women at risk for CVD, 3 weeks of consuming an
ad libitum low-fat, high-complex-starch, high-fiber diet,
in combination with daily moderate-to-vigorous aerobic
exercise, reduced cholesterol by 23% (from 234 to 180 mg/
dL), LDL-C by 23% (from 151 to 116 mg/dL), and tri-
glycerides by 32.5% (from 200 to 135 mg/dL).67 Although
this intervention reduced body weight (4%–5%) by more
than the interventions mentioned above, correlations between
changes in lipids and changes in body weight ranged between
0.07 and 0.17, suggesting that very little of the decrease
in cholesterol or triglycerides could be attributed to decreases
in body weight.
For comparison, studies of intentional weight loss in
obese men and women indicate that weight loss of 8% to
10% reduces total cholesterol by approximately 9%, LDL-C
by 5% to 11%, and triglycerides by 16% to 27%.12,47 Greater
weight loss (∼15%) may reduce triglycerides by even more
(44.5%).13 In 1 study, however, weight loss itself was found to
be a weak predictor of reductions in triglycerides (r = 0.18).13
Endothelial Function
Endothelial function appears to play a key role in the
pathogenesis of atherosclerosis and is considered the first
step in the genesis of atherosclerosis. It is also a strong
and independent predictor of cardiovascular morbidity and
mortality.68 It has been suggested that weight loss of approxi-
mately 10% may be necessary to significantly improve endo-
thelial function.69,70 In overweight/obese adults, weight loss
of 10.6% improved brachial artery flow-mediated dilation
(FMD) by 30%.69 Among severely obese patients who lost
© The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847
Weight Loss-Independent Effects of Exercise and Diet
27.6% body weight by diet and/or bariatric surgical interven-
tion, brachial artery FMD was improved by 47%.71 However,
both aerobic and resistance exercise training, in the absence
of weight loss, have been reported to improve endothelium-
dependent vasodilation in a number of populations.63,72–74
In men and women with metabolic syndrome, 12 weeks of
either aerobic interval training, resistance exercise training,
or combined training increased brachial artery FMD by 28%
to 38% in all groups, despite no change in body weight.73
Although both aerobic and resistance training groups reduced
body fat modestly (1.9–2.1 kg; 6%–7%), the combined train-
ing group had no statistically significant reduction in body
fat (0.8 kg; 2.4%), yet had the greatest improvement (∼38%)
in brachial artery FMD. This suggests that the reduction in
body weight or body fat was not responsible for the improve-
ments in endothelial function. In 1 study, a 1-year period
of resistance exercise training in overweight women was
reported to increase brachial artery FMD by 41%, without a
reduction in total body fat mass.72
In 1 study, it was demonstrated that 8 weeks of aerobic
exercise training increased forearm vasodilatory response to
acetylcholine by 56% in overweight men and women and by
41% in obese men and women with type 2 diabetes, despite
there being no changes in body weight or fat mass.63 In obese
adults with type 2 diabetes, 4 weeks of aerobic training and
a hypocaloric diet reduced body weight by 6.1% (6 kg), but
had no effect on coronary vasodilation.75 Interestingly, after
an additional 5 months of training, during which time body
weight had increased by 3.1 kg (ie, ~50% weight regain
from the 4-week weight-loss peak), coronary blood flow in
response to acetylcholine infusion increased by 127% and,
in response to adenosine infusion, increased by 58.7%. Such
significant improvements in coronary endothelial function
achieved during a period of weight gain of 3.1 kg suggests
that exercise training may be more important than weight
loss for improving vascular health.
Three months of close adherence to a Mediterranean diet
improved brachial artery FMD by 50% in abdominally obese
adults.76 The modest (2.7 kg; 2.9%) weight loss achieved after
the intervention likely did not explain the results because a
comparison diet group lost a similar amount of weight (2.1 kg;
2.2%) yet experienced no change in endothelial function. In an
8-week study of obese men and women with type 2 diabetes,
an ad libitum diet supplemented with walnuts (56 g/day)
resulted in a 25.6% increase in brachial artery FMD, despite
no changes in body weight or waist circumference.77 The
suggestion that diet quality is more important than weight loss
itself is exemplified by the fact that a low-carbohydrate diet
91
 Gaesser et al
has been reported to induce weight loss but impairs endothelial
function.78 In overweight or obese men and women, a 1-year
period of a low-carbohydrate diet reduced body weight by
14.9 kg (15.8%), yet impaired brachial artery FMD by 35%.78
Hemostasis
Type 2 diabetes and CVD result in an inability to degrade
arterial plaque and control blood coagulation. Matrix
metalloproteinases (MMPs) and their inhibitors (tissue
inhibitors of metalloproteinases [TIMPs]) are a fam-
ily of endopeptidases that have proteolytic properties.79
Data on humans suggest that MMP-2 and MMP-9 can
mediate atherogenesis, control plaque disruption, and
cause plaque hypercoagulability.80 In a 16-week, home-based
aerobic exercise intervention of  150 minutes per week
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in 25 sedentary, overweight subjects with type 2 diabetes,
MMP-9 was reduced by 32% and TIMP-2 was increased by
18%.28 Furthermore, the intervention lowered the MMP-9/
TIMP-1 ratio by 33%, which is an independent predictor of
coronary artery disease (CAD) severity.81 The improvements
seen in pro- and antiatherogenic markers were combined with
a 17% decrease in fibrinogen and a 30% decrease in C-reac-
tive protein (CRP), despite no change in BMI.28 Similarly,
12 weeks of supervised endurance exercise in patients with
known CAD and/or CVD risk factors reduced MMP-9 by
18%, with only a very modest reduction in BMI (0.4 units).82
For comparison, weight loss of 12% to 13% (13–15 kg)
after 8 weeks on a very low-energy diet with or without
orlistat increased MMP-9 by 23%.51 After 3.2 years of
follow-up in this study, sustained weight loss of 6% to 9%
was associated with reduction in MMP-9 from a baseline of
17% to 34%,50 which is comparable with the reductions seen
with endurance exercise training, with no change28 or modest
(1.5%) change82 in BMI.
Overweight and obese individuals typically have impaired
endothelial control of fibrinolysis, particularly because of
insufficient release of tissue plasminogen activator. In a
study of overweight and obese adults, 3 months of aerobic
exercise training (40–50 min at 60%–75% maximal heart rate,
5–7 days/week) improved tissue plasminogen activator release
by 55%, to the same levels as nonoverweight controls.83
The training did not reduce body weight, body fat, or waist
circumference, which suggests that the impaired fibrinolytic
control was linked to the sedentary lifestyle and not the excess
body weight.83 We are unaware of any effect of weight loss
on vascular endothelium tissue plasminogen activator release.
Dietary modifications with little to no weight loss have
also been shown to improve hemostatic factors in diseased
92 © The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847
populations.34,57 In a sample of 49 asymptomatic subjects at
high risk for CVD, Llorente-Cortés et al57 found that when
patients consumed a Mediterranean diet with added nuts and
that was high in monounsaturated fatty acids, polyunsaturated
fatty acids, and various bioactive compounds for a 3-month
period, this tissue factor pathway inhibitor was increased by
by 39%, despite no changes in body weight. Tissue factor
pathway inhibitor is known to decrease blood coagulation
and reduce restenosis of arteries.84,85 The authors concluded
that a Mediterranean diet with added nuts may cause vascu-
lar remodeling.57 In contrast, tissue factor pathway inhibitor
activity was decreased by 7% after weight loss of 32% via
gastroplasty.86
Plasminogen activator inhibitor-1 (PAI-1), which inhibits
the activation of fibrinolysis, has been shown to increase in
obese populations.48 In 1 study, 10 weeks of a low-glycemic
diet decreased PAI-1 by 15% in overweight women, despite
minimal weight loss (−1.9 kg).34 The fact that PAI-1 activity
was not changed in women who consumed a high-glycemic
diet, despite similar weight loss (−1.3 kg), suggests that
the improvement was attributable to diet quality rather
than weight loss itself. However, substantially greater
diet-induced weight loss (8%–10%) has been shown to
reduce PAI-1 by 31% to 38%, which suggests that weight loss
does play a role.48,51 It is important to note that the addition of
exercise to a hypocaloric diet produced a 71% reduction in
PAI-1,48 which suggests that both exercise and weight loss are
contributing factors. Adipose tissue hypoxia associated with
obesity has been shown to result in increased gene expres-
sion of PAI-1 in cell lines.87 Adipose tissue hypoxia can be
ameliorated by both weight loss and exercise.87 At this point,
however, it is not clear if one strategy is superior to the other.
Inflammation
Cardiovascular disease and type 2 diabetes have been shown
to be characterized by low-grade inflammation.88 Low-
grade inflammation is detected by elevations in numerous
pro-inflammatory biomarkers, including CRP, interleukin
(IL)-6, tumor necrosis factor alpha (TNF-α), IL-18, IL-1β,
interferon-γ (IFN- γ ), CD14+, CD16+, CD49d, CD40, and
E-selectin, or by lower levels of anti-inflammatory biomarkers
such as IL-4, IL-10, and adiponectin. Although weight loss
has been reported to affect inflammatory molecules, it
has been demonstrated that inflammatory status can be
improved with exercise and/or diet in the absence of weight
loss.29,32,35,36,44,82,89–93 In a study of men and women with type 2
diabetes, 12 months of either aerobic or combined aerobic and
resistance exercise training significantly reduced CRP, IL-1β,

IL-6, TNF-α, and IFN-γ, and increased IL-4, IL-10, and
adiponectin.44 Body weight was not reduced in either group,
indicating that exercise training has a full anti-inflammatory
effect that is indepdendent of weight loss.44
In contrast, significant weight loss (9%–10%) after a
hypocaloric diet did not reduce CRP.49,51 As a result, Madsen
et al49 concluded that weight loss of  10% is necessary
to significantly improve inflammatory markers in obese
individuals. However, in a study of overweight men and
women with type 2 diabetes, 6 months of aerobic training
(4 days/week, 45–60 min/session at 50%–75% peak oxygen
consumption) reduced CRP by 39%, IL-18 by 35%, and IL-18/
IL-10 ratio by 50%, and increased anti-inflammatory marker
IL-10 by 43%.29 Body weight and fat mass were not reduced.
The weight-loss–independent effect of exercise training
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is best exemplified by Milani et al,89 who studied 235
patients with coronary heart disease before and after cardiac
rehabilitation. Patients who lost weight (6 lb; 3% of initial
body weight) reduced their CRP levels by 31%; patients who
gained weight (6 lb; 3% of initial body weight) also reduced
their CRP levels by 42%. Furthermore, Lambert et al90
reported that significant weight loss (7.5 kg) via diet had no
effect on markers of muscle inflammation, whereas exercise
training in the absence of weight loss reduced Toll-like recep-
tor-4 mRNA by 37% and IL-6 and TNF-α mRNA by 50%.
Thus, body weight/body fat loss itself does not appear to be
the cause of the reduction in low-grade inflammation observed
after lifestyle interventions involving exercise and diet.
Dietary interventions, in the absence of weight loss, have
also been shown to improve inflammatory status.32,36,91–93 In
overweight/obese adults at high risk for CVD, 3 months
of a Mediterranean diet supplemented with either virgin
olive oil (1 L/week) or nuts (30 g/day) significantly reduced
proinflammatory markers CD49d, CD40, and IL-6, with a
reduction in CRP observed only in the diet supplemented with
virgin olive oil.36 Both diets also significantly reduced IL-6,
vascular cell adhesion molecule-1, and intercellular adhesion
molecule-1.32 Body fat was unchanged. Similarly, studies that
replaced typical Western protein products high in saturated
fats (ie, red meat) with other protein-rich foods (eg, soy92
and almonds93) have shown decreases in proinflammatory
markers, including E-selectin,92,93 IL-18,92 and CRP,92,93 yet
there were no changes in body weight.
Skeletal Muscle Adaptations
with Exercise Training
Aerobic exercise training results in skeletal muscle adaptations,
including increases in mitochondrial enzymes, overall
© The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847
Weight Loss-Independent Effects of Exercise and Diet
mitochondrial function, and increases in capillarization,
which are highly related to improvements in insulin
sensitivity as well as carbohydrate and lipid disposal.22,39,42
Two recent studies demonstrated that 12 weeks of combined
resistance and endurance exercise training in overweight/
obese men with type 2 diabetes restored mitochondrial
function to the level of healthy control subjects, despite
there being no changes in body weight and only minimal
changes in body fat ( 1.5 kg).39,42 In vivo mitochondrial
function was significantly lower in the type 2 diabetes
group before training, but improved by 48% after 12
weeks of training to a similar level as the control group.
In addition, insulin sensitivity was increased by 63%.42 In
a subset of this population, ex vivo mitochondrial function
was increased by 33% to a level that was not significantly
different than that of the nondiabetic controls matched for
age and BMI.39
Weight loss does not improve skeletal muscle
mitochondrial capacity.94 However, 1 study demonstrated
that just 10 consecutive days of aerobic exercise in both
obese women and formerly obese women increased skeletal
muscle fat oxidation capacity and the mRNA content for
pyruvate dehydrogenase kinase-4, carnitine palmitoyltrans-
ferase 1, and peroxisome proliferator-activated receptor-γ
coactivator-1α.94 Thus, skeletal muscle mitochondrial defects
evident with obesity can be corrected with exercise training
but persist after weight loss.
Exercise training may also change lipid composition in
skeletal muscle. In a study of 9 obese men and women, 8
weeks of moderate-intensity endurance training (five 60-min
sessions/week at 65%–70% peak oxygen consumption)
increased activities of several mitochondrial enzymes by
36% to 250%, and more than doubled (120% increase)
skeletal muscle fatty acid oxidation.22 Additionally, training
marginally (P = 0.06) reduced total muscle diacylglycerol
content by 15% and saturated DAG content by 27%, and
reduced total muscle ceramide content by 42% and saturated
ceramide species by 32%. The reductions in diacylglycerol
fatty acids were significantly correlated with improvements
in insulin sensitivity, which is consistent with the view
that muscle ceramide content may play a role in insulin
resistance.95 These exercise training-induced reductions in
skeletal muscle diacylglycerol and ceramide content occurred
despite no reduction in body weight.
Postprandial Metabolism
Exaggerated postprandial lipemia and decline in endothelial
function due to a high-fat meal may be important factors
93
 Gaesser et al
in atherosclerotic plaque formation and development of
metabolic syndrome. Both exercise and weight loss reduce
postprandial lipemia, although much of the weight-loss effect
may be due to negative energy balance rather than weight
loss itself.96 Exercise training in the absence of weight loss
reduces both fasting and postprandial triglyceridemia.97 Even
acute exercise in the absence of habitual training improves
the postprandial response to a high-fat meal.43,98,99 In obese
men with metabolic syndrome, 60 minutes of exercise at
either 40%, 60%, or 70% of maximal oxygen consump-
tion performed 12 hours before ingestion of a fat-rich meal
attenuated postprandial triglyceridemia by 30% to 40%.43
These postprandial reductions in triglycerides after 1 exercise
session are comparable with those observed after 7 weeks
of exercise training,97 suggesting that much of the apparent
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training adaptation may be due to the effects of the most
recent exercise session.
Although acute exercise may not always attenuate
postprandial triglyceridemia, exercise may provide protection
against endothelial dysfunction that is typically observed fol-
lowing ingestion of a high-fat meal.99 In overweight men, 1
session of high-intensity aerobic interval exercise 16 hours prior
to ingestion of a high-fat meal completely abolished the impair-
ment in endothelial function that occurred after ingestion of the
high-fat meal without prior exercise.99 The mechanism may
be linked to blood total antioxidant status, as this was highly
correlated (r = 0.90) with postprandial brachial artery FMD.
Conclusion
The marked improvements in cardiometabolic risk profiles
of overweight and obese individuals accompanying exercise
and diet interventions, even in the absence of clinically sig-
nificant weight loss, may help to explain the findings in a
number of observational studies that aerobic fitness greatly
attenuates mortality risk in overweight/obese individuals.100
A recent review demonstrated that the risk for all-cause and
CVD-related mortality was lower in individuals with high
BMI and good aerobic fitness compared with individuals
with normal BMI and poor fitness.100 The importance of
these findings must be viewed in the context of the poor
results of weight-loss interventions and long-term weight
maintenance.3,4
Although the cardiovascular and metabolic benefits of
weight loss in overweight/obese patients are well docu-
mented,1,2,12–19,47–50 the high recidivism rates for weight-loss
interventions4 suggest that these benefits are not sustained.52
In the past 30 years, the prevalence of obesity has doubled;
in addition, the prevalence of weight-loss attempts (mostly
94 © The Physician and Sportsmedicine, Volume 39, Issue 2, May 2011, ISSN – 0091-3847
via calorie restriction) has remained consistently high.5 An
estimated 60% to 70% of obese men and women in the
United States attempt weight loss each year.5 Thus, calorie
restriction approaches to weight management do not appear
to have been very successful. Furthermore, the weight fluc-
tuation that typifies chronic attempts to lose weight may not
be benign.6–8 Instability of metabolic risk factors (eg, fasting
insulin, non–HDL-C/HDL-C ratio) has been reported to be
a significant predictor of atherosclerotic vascular disease,6
which may explain in part the higher CVD mortality rate
associated with weight fluctuation.8
Although weight loss is a desired outcome for many
overweight/obese persons, we contend that it may be
more prudent to focus on increasing physical activity and
improving diet quality rather than focusing on a specific
weight-loss goal. For example, data from the FDPS15 and
DPP16 indicate that 50% to 100% more participants were able
to achieve the physical activity target (150 min/week in the
DPP; 210 min/week in the FDPS) than were able to achieve
the weight-loss goal ( 7% loss of initial body weight in the
DPP;  5% loss of initial body weight in the FDPS). Thus,
for at-risk populations (eg, sedentary individuals with a high
BMI), it may be easier to increase fitness than to decrease
fatness.
Most of the beneficial adaptations to exercise training
described in this article can be attained with relatively moder-
ate-intensity effort, equivalent to brisk walking.10,22,30,37,43,54,55,72
This is particularly true for improving glucose metabolism
and insulin action,37 and for lowering blood pressure.30,54
It is also important to emphasize that exercise training
adaptations can occur rapidly, within  7 to 10 days,26,94 and
that even single exercise sessions have acute benefits that can
persist for hours (eg, blood pressure reduction101) or days
(eg, enhanced insulin action40). Exercise sessions as short
as 10 minutes can lower blood pressure, and fractionizing
exercise bouts into multiple 10-minute sessions per day may
be more effective than a single 30-minute session of exercise
for lowering systolic blood pressure throughout the day.101
Similarly, dietary strategies that focus on increasing con-
sumption of nutrient-dense foods (eg, fruits, vegetables, whole
grains, and nuts) without an arbitrary weight-loss goal, such as
the DASH58,59 and Mediterranean20,32,36,66,76 diets, may produce
more long-lasting health benefits and avoid the pitfalls of
calorie-restrictive approaches that may lead to chronic weight
fluctuation. Because there does not appear to be a clinically
significant minimum level of weight-loss that must be reached
to produce clinical benefits,14 specific weight loss goals may
be unnecessary. Indeed, the mere intention to lose weight,

even if unsuccessful, has been reported to be associated with
a reduction in 9-year mortality risk in overweight adults with
type 2 diabetes.102 This might be explained by the adoption of
a healthier lifestyle that did not induce weight loss.
From a public health perspective, it is essential to
emphasize that overweight/obese individuals with risk
factors for type 2 diabetes and CVD can reap important
cardiometabolic benefits from physical activity and healthy
eating regardless of changes in adiposity. Thus, overweight/
obese individuals considered at increased risk for CVD and
type 2 diabetes due to sedentary lifestyle, poor diet, and a
high BMI should be encouraged to engage in regular physical
activity and consume a more nutrient-dense diet, regardless
of whether the healthier lifestyle leads to weight loss.
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Conflict of Interest Statement
Glenn A. Gaesser, PhD, Siddhartha S. Angadi, BOTh, and
Brandon J. Sawyer, MEd disclose no conflicts of interest.
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