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1. Effect of Short-Term Weight Loss on the
Metabolic Syndrome and Conduit
Vascular Endothelial Function in
Overweight Adults
Robert D. Brook, MD, Robert L. Bard, MA, Lynn Glazewski, RD, Christine Kehrer, RVT,
Peter F. Bodary, PhD, Daniel L. Eitzman, MD, and Sanjay Rajagopalan, MD
Impaired vascular endothelial function may be an im-
portant mechanism linking obesity to increased cardio-
vascular risk. We investigated whether short-term
weight loss improves conduit artery endothelial dysfunc-
tion in overweight adults. Forty-three otherwise healthy
overweight patients with a body mass index >27 kg/m2
completed an open-label 3-month trial consisting of a
calorie-restricted diet and 120 mg of orlistat taken 3
times daily with meals. Endothelial function and param-
eters of the metabolic syndrome were measured before
and after intervention. Subjects lost 6.6 ؎ 3.4% of their
body weight. Low-density lipoprotein cholesterol, low-
density lipoprotein concentration, fasting insulin, and
leptin decreased significantly (all p <0.009), and C-re-
active protein decreased (p ‫؍‬ 0.22). Conduit vascular
function did not change as assessed by flow-mediated
dilation (3.86 ؎ 3.54 vs 3.74 ؎ 3.78%, p ‫؍‬ 0.86) and
nitroglycerin-mediated dilation (17.18 ؎ 5.89 vs 18.87
؎ 7.11%, p ‫؍‬ 0.13) of the brachial artery. A moderate
degree of weight reduction over 3 months improved the
metabolic syndrome profile but not the vascular dysfunc-
tion associated with uncomplicated obesity. ᮊ2004 by
Excerpta Medica, Inc.
(Am J Cardiol 2004;93:1012–1016)
Impaired vascular endothelial function due to the
adverse effects of the metabolic syndrome may be
an important mechanism linking obesity to increased
cardiovascular risk.1,2 In addition, adipose tissue has
the capacity to directly trigger endothelial dysfunction
by secreting a variety of molecules (e.g., proinflam-
matory cytokines1 and leptin1–5). Several of these cy-
tokines mediate the release of C-reactive protein
(CRP) from the liver, which also may impair endo-
thelial function.6 Weight loss has been shown to im-
prove the function of the resistance vasculature arte-
rial endothelium and decrease circulating markers of
endothelial damage.7–9 However, its effect on conduit
vascular function has not been reported. The primary
aim of this study was to determine whether short-term
weight reduction could improve the conduit (brachial)
arterial endothelial function associated with uncom-
plicated obesity. In addition, we investigated the rela-
tion across changes in the various parameters of the
metabolic syndrome, CRP, plasma leptin, and arterial
endothelial function induced by weight loss.
METHODS
Human subjects: Potential subjects were recruited
by local advertisements. Subjects were included if
they were 18 to 50 years old, were overweight as
defined by a body mass index Ն27 kg/m2
, and had a
waist-to-hip ratio Ն0.80 for women and Ն0.85 for
men. All subjects were apparently healthy by history
and physical examination. Subjects were excluded for
blood pressure Ͼ140/90 mm Hg, fasting total choles-
terol Ͼ240 mg/dl, fasting glucose Ͼ126 mg/dl, or
thyroid stimulating hormone Ͼ5.5 mU/L. All women
had a negative pregnancy test before the trial. Other
exclusion criteria were cardiovascular disease, cardio-
vascular risk factors other than obesity, medications
for hypertension, hyperlipidemia, thyroid dysfunction,
contraception use, or hormone replacement. Subjects
were also excluded for other factors that could influ-
ence endothelial function (e.g., current tobacco use,
antioxidants, folate, and fish oil). Subjects were in-
structed to maintain the same physical activity
throughout the trial and were not permitted to initiate
an exercise program.
Study protocol: The study was approved by the
institutional review board at the University of Michi-
gan Medical School, and each subject gave written
informed consent. After an initial screening visit, sub-
jects participated in a 12-week open-label weight-loss
trial of dietary counseling plus 120 mg of orlistat 3
times daily with meals. The intervention included a
calorie-restricted diet and orlistat, a pancreatic lipase
inhibitor, because of its proved efficacy versus diet
alone.10
Experimental end points: Subjects fasted for Ն8
hours before testing. Endothelial function, anthropo-
metric measurements, blood laboratory results, and an
oral fat tolerance were assessed at baseline and 12
weeks after treatment in each subject, in the same
order, and at the same time of day at the 2 visits.
From the Division of Cardiovascular Medicine, University of Michigan,
Ann Arbor, Michigan. This study was funded by grants from Roche
Pharmaceuticals (XEN 167), Nutley, New Jersey, and the General
Clinical Research Center at the University of Michigan (MO1-
RR00042), Ann Arbor, Michigan. Manuscript received August 27,
2003; revised manuscript received and accepted December 31,
2003.
Address for reprints: Robert D. Brook, MD, 3918 Taubman Cen-
ter, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109.
E-mail: robdbrok@umich.edu.
1012 ©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matter
The American Journal of Cardiology Vol. 93 April 15, 2004 doi:10.1016/j.amjcard.2004.01.009

2. Conduit vessel endothelial function was the pri-
mary end point and was determined by brachial arte-
rial flow-mediated dilation (FMD) measured with
high-resolution vascular ultrasonography. Nitroglyc-
erin-mediated dilation (endothelial-independent vaso-
motion) also was determined as previously de-
scribed.11 Subjects rested in a supine position in a
temperature-controlled room for Ն15 minutes before
each vascular study. Validation studies in 25 healthy
subjects performed in the same laboratory demon-
strated a high degree of FMD reproducibility consis-
tent with published literature.2
Waist (thinnest abdominal circumference below
the xiphoid process), hip (circumference at the level of
the femoral heads), and waist cir-
cumference (circumference at the
level of the iliac crest) measurements
were obtained from each subject.
Percent body fat was calculated as
the average of the values obtained by
bioelectrical impedance and skinfold
thicknesses at 3 sites12 (triceps,
thigh, and suprailiac in women;
chest, abdomen, and thigh in men).
Blood was drawn for fasting lev-
els of glucose, insulin, lipoprotein
subfractions, CRP, and leptin, and
then subjects performed a 6-hour
oral fat tolerance test. Baseline tri-
glyceride and insulin levels were
measured before each subject con-
sumed a milkshake containing 50 g
of fat/m2
of body surface area. Sub-
jects drank the shake over 5 to 10
minutes, and triglycerides were mea-
sured at hours 2, 4, and 6 while sub-
jects refrained from physical activity
and food consumption.
CRP, lipoproteins, and leptin
measurements: CRP and lipoprotein
subclass levels (very-low-density li-
poprotein [LDL] cholesterol, high-
density lipoprotein cholesterol, LDL
cholesterol, their patient particle di-
ameters, and LDL particle concentra-
tion) were measured by LipoScience
Incorporated (Raleigh, North Caro-
lina). Lipoproteins were analyzed by
nuclear magnetic resonance spectros-
copy, and high-sensitivity CRP was
analyzed by the Immuline 2000 ana-
lyzer (Diagnostic Product Corporation,
Los Angeles, California), as described
elsewhere.13
Plasma leptin concentration was
measured with a commercially avail-
able enzyme-linked immunosorbent
assay kit (Linco Research, St. Louis,
Missouri) according to the manufac-
turer’s instructions. The intra-assay
coefficient of variation was 4.1%.
Dietary intervention: All dietary
counseling and analyses were performed and stan-
dardized by the same registered dietician. A detailed
3-day food diary was collected and analyzed for intake
of kilocalories, carbohydrates, proteins, fats, saturated
fats, polyunsaturated fats, monounsaturated fats, vita-
mins, minerals, caffeine, and alcohol at baseline and
completion of the study (Elizabeth Stuart Hands and
Associates Food Processor 7.6 for Windows, ESHA
Research, Salem, Oregon). Subjects were instructed to
consume a moderately calorie-restricted diet during
the study. Each subject was prescribed a diet that was
500 calories less than weight-maintenance needs, with
30% of calories coming from fat. If maintenance en-
ergy requirements were Ͻ1,500 calories/day, caloric
FIGURE 1. The effects of 3 months of weight-loss therapy on body mass index, waist
circumference, percent fat, and body weight. Boxes, the first and third quartiles; bars,
the median values; and whiskers, the minimum and maximum values. Mean ؎ SD is
presented above each plot. Paired t tests showed significant differences in body mass
index (p <0.001), waist circumference (p ‫؍‬ 0.001), percent fat (p ‫؍‬ 0.007), and
body weight (p <0.001).
TABLE 1 Metabolic and Blood Pressure Responses to Weight Reduction
Baseline
Post-Treatment
(12 wks) p Value
Serum total cholesterol (mg/dl) 177 Ϯ 32 164 Ϯ 31 0.002*
Serum triglycerides (mg/dl) 114 Ϯ 64 106 Ϯ 64 0.208
Serum high-density lipoprotein (mg/dl) 46 Ϯ 10 44 Ϯ 10 0.029*
Serum LDL (mg/dl) 114 Ϯ 27 104 Ϯ 25 0.005*
Total cholesterol/high-density lipoprotein 3.96 Ϯ 0.96 3.84 Ϯ 0.94 0.185
LDL particle size (nm) 20.56 Ϯ 0.67 20.57 Ϯ 0.60 0.900
LDL particle concentration (mmol/L) 1,339 Ϯ 359 1,222 Ϯ 325 0.009*
High-density lipoprotein particle size (nm) 8.74 Ϯ 0.32 8.80 Ϯ 0.36 0.107
Blood glucose (mg/dl) 88.3 Ϯ 6.8 85.5 Ϯ 9.2 0.069
Insulin (UU/ml) 8.8 Ϯ 4.1 7.4 Ϯ 2.7 0.002*
CRP (mg/dl) 0.47 Ϯ 0.41 0.40 Ϯ 0.45 0.226
Systolic blood pressure (mm Hg) 121 Ϯ 13 120 Ϯ 16 0.538
Diastolic blood pressure (mm Hg) 69 Ϯ 10 68 Ϯ 9 0.452
Baseline values versus values after treatment by paired-samples t test.
*p Ͻ0.05.
MISCELLANEOUS/WEIGHT LOSS AND VASCULAR FUNCTION 1013

3. deficit was adjusted to provide no fewer than 1,000
calories/day.
Subjects faxed or e-mailed detailed food records
daily and received instruction, feedback, and support
by the dietitian by telephone or e-mail. Subjects also
had formal one-on-one nutrition counseling for at least
1 hour with the dietician every 4 weeks.
Statistical analyses: Paired-samples t tests were
used to compare the effect of the weight-loss inter-
vention on different variables. Univariate Pearson’s
correlation coefficients were obtained between study
variables and changes in FMD, nitroglycerin-medi-
ated dilation, and arterial compliance. Given the ex-
pected 3.5% SD in FMD from our laboratory, we had
80% power to determine a 1.5% change in FMD after
weight loss in 43 subjects. Statistical significance was
defined as p Ͻ0.05.
RESULTS
Seventy-one subjects completed the initial assess-
ment and were enrolled into the trial. Ten men and 33
women (43 subjects) completed the study and the 2
assessments of vascular function. Only 1 subject left
the trial because of an adverse event, abdominal
cramping associated with the medication. Seven other
subjects dropped out of the study because of their
inability to adhere to the restricted fat content of the
diet, which resulted in fecal urgency and oily stools.
The remaining subjects were unavailable or unwilling
to complete the final assessment. The mean age for the
43 subjects who completed the study was 38 Ϯ 8
years.
The average daily meal compositions at baseline
versus those at study completion were 2,216 Ϯ 722
versus 1,622 Ϯ 409 total calories, 35 Ϯ 6% versus 29
Ϯ 7% calories from fat, 11.2 Ϯ 2.9% versus 1.1 Ϯ
0.0% calories from saturated fat, 1.0 Ϯ 0% versus 0.5
Ϯ 1.0% calories from monounsaturated fat, and 0.5 Ϯ
0.3% versus 0.6 Ϯ 0.1% calories from polyunsatu-
rated fat.
After 12 weeks, subjects lost an average of 6.6 Ϯ
3.4% of their initial body weight, and 9 of 43 subjects
lost Ն10%. All anthropometric measurements were
significantly decreased (Figure 1). Overall, weight
loss lessened the metabolic syndrome. Insulin, LDL
particle concentration, LDL cholesterol, and high-den-
sity lipoprotein cholesterol decreased significantly,
whereas fasting glucose, CRP, and high-density li-
poprotein size trended toward improvement (Table 1).
Despite these changes, brachial artery FMD, brachial
nitroglycerin-mediated dilation (Figure 2), and blood
pressure (Table 1) remained the same.
Oral fat tolerance improved modestly after inter-
vention (Figure 3). The 2-hour postprandial increase
in triglycerides was significantly decreased at study
completion compared with the 2-hour postprandial
increase at baseline. All other postprandial triglycer-
ide levels and the area under the triglyceride curve did
not change significantly as a result of the intervention.
Plasma leptin concentration decreased significantly
after weight loss (Figure 4). This decrease in plasma
leptin positively correlated with the change in FMD
after weight loss (Figure 5). There were no other
significant correlations between the changes in FMD
FIGURE 2. The effects of 3 months of weight-loss therapy on FMD
and nitroglycerin-mediated dilation (NMD). Boxes, the first and
third quartiles; bars, the median values; and whiskers, the mini-
mum and maximum values. Mean ؎ SD is presented above each
plot. Paired t tests showed no significant differences in FMD (p ‫؍‬
0.857) or NMD (p ‫؍‬ 0.129).
FIGURE 3. Triglyceride concentrations throughout the oral fat tol-
erance test before and 12 weeks after weight loss.
1014 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 93 APRIL 15, 2004

4. or nitroglycerin-mediated dilation and any other study
measurement.
DISCUSSION
Orlistat-assisted weight reduction improved the
metabolic syndrome profile of overweight adults after
3 months. LDL particle concentration also decreased
significantly (Table 1). Despite the substantial meta-
bolic benefits, a 6.6% body weight reduction over 3
months did not lessen conduit (brachial) arterial en-
dothelial dysfunction (Figure 2).
A novel observation in this study was that the
change in endothelial function after weight loss was
predicted only by the change in plasma leptin concen-
tration (Figure 5). From this finding and the ability of
leptin to mediate endothelium-dependent vasodilation
by the release of nitric oxide,4–7 it is plausible to
speculate that the reduction in leptin may have blunted
the expected improvement in FMD. This is the first
observation to suggest that leptin positively modulates
vascular endothelial function in humans. Further stud-
ies are required to directly test this hypothesis.
In at least 3 previous articles, endothelial function
improved after comparable amounts of weight loss.7–9
The reasons for the discrepancy between our results
and those of previous reports are not entirely clear, but
small differences in the dietary prescriptions may have
played a role. However, the dietary changes in our
study (e.g., reductions in total and saturated fats)
would be expected to improve vessel function. There
were no other significant dietary nutrient or antioxi-
dant changes observed in our study that could account
for our results. Although we cannot exclude the pos-
sibility, it is unlikely that the use of orlistat was
responsible. No significant effects on fat-soluble vita-
mins, plasma antioxidants, or other nutrients have
been reported from larger weight-loss studies using
orlistat10 that would be expected to impair FMD. The
very small reduction in mean high-density lipoprotein
cholesterol among our subjects could have played a
role. However, this also seems unlikely given the
substantial improvements in most other components
of the metabolic syndrome (Table 1) and all other
lipoprotein factors (e.g., total cholesterol/high-density
lipoprotein ratio) and the reduction in postprandial
lipemia.
The most probable explanation is that this is the
first study to report the effect of weight loss on conduit
(brachial) arterial endothelial function. In previous
experiments, endothelial function was measured at the
resistance arteriole level8,9 or by the plasma concen-
trations of soluble adhesion molecules.14 Vascular
function may vary within the same patient when de-
termined by different methodologies using different
stimuli and at different vascular territories.15 There-
fore, the lack of improvement in conduit vessel endo-
thelial function instigated by shear stress (brachial
FMD) does not contradict prior investigations that
demonstrated enhanced endothelial-dependent flow at
the resistance arteriole level after receptor agonist-
mediated stimulation.8,9
The implication from our findings is that, although
resistance vessel endothelial function may improve,
comparable time periods, dietary changes, and
amounts of weight loss may not be capable of restor-
ing conduit artery function. Although adequately pow-
ered (80%) with our sample size (n ϭ 43) to determine
a 1.0% change in FMD, improvements in conduit
FIGURE 4. The effects of 3 months of weight-loss therapy on lep-
tin levels. Boxes, the first and third quartiles; bars, the median
values; and whiskers, the minimum and maximum values. Mean
؎ SD is presented above each plot. Paired t test of the differ-
ences in leptin before and after weight loss was significant.
FIGURE 5. Correlations between the change in leptin after weight
loss with the changes in FMD (*p ‫؍‬ 0.05) and nitroglycerin-me-
diated dilation (NMD) of the brachial artery (p ‫؍‬ NS).
MISCELLANEOUS/WEIGHT LOSS AND VASCULAR FUNCTION 1015

5. endothelial function may be seen with more subjects
for a longer time and/or after a greater weight loss.
An additional study on weight loss and endothelial
function has also been published. Raitakari et al16
demonstrated an improvement in brachial artery FMD
(from 5.5 Ϯ 3.7% to 8.8 Ϯ 3.7%, p Ͻ0.0001) in 67
nondiabetic, obese adults after following a very low
calorie diet (daily energy intake of 580 kcal/2.3 MJ)
for 6 weeks. The increase in FMD was only related to
a decrease in blood glucose and occurred indepen-
dently of all other metabolic improvements. As in our
study, there was no relation between the change in
FMD and the overall similar amount of weight loss
observed (11 kg). The only substantial difference
among studies that can potentially explain their dif-
ferent findings is the extremely low-calorie diet.
Taken together with our results, it appears that the
lifestyle changes and diet used to achieve weight loss
appear to be more important determinants of the
change in vascular function than the actual decrease in
adiposity.
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