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Effect of Obesity on High-density Lipoprotein Metabolism**

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Review
Effect of Obesity on High-density Lipoprotein
Metabolism
Shirya Rashid and Jacques Genest
Abstract
RASHID, SHIRYA, JACQUES GENEST. Effect of obesity
on high-density lipoprotein metabolism. Obesity. 2007;15:
2875–2888.
Reduced levels of high-density lipoproteins (HDL) in non-
obese and obese states are associated with increased risk for
the development of coronary artery disease. Therefore, it is
imperative to determine the mechanisms responsible for
reduced HDL in obese states and, conversely, to examine
therapies aimed at increasing HDL levels in these individ-
uals. This paper examines the multiple causes for reduced
HDL in obese states and the effect of exercise and diet—
two non-pharmacologic therapies— on HDL metabolism in
humans. In general, the concentration of HDL-cholesterol is
adversely altered in obesity, with HDL-cholesterol levels
associated with both the degree and distribution of obesity.
More specifically, intra-abdominal visceral fat deposition is
an important negative correlate of HDL-cholesterol. The
specific subfractions of HDL that are altered in obese states
include the HDL2, apolipoprotein A-I, and pre-␤1 subfrac-
tions. Decreased HDL levels in obesity have been attributed
to both an enhancement in the uptake of HDL2 by adipo-
cytes and an increase in the catabolism of apolipoprotein
A-I on HDL particles. In addition, there is a decrease in the
conversion of the pre-␤1 subfraction, the initial acceptor of
cholesterol from peripheral cells, to pre-␤2 particles. Con-
versely, as a means of reversing the decrease in HDL levels
in obesity, sustained weight loss is an effective method.
More specifically, weight loss achieved through exercise is
more effective at raising HDL levels than dieting. Exercise
mediates positive effects on HDL levels at least partly
through changes in enzymes of HDL metabolism. Increased
Received for review January 17, 2007.
Accepted in final form May 3, 2007.
The costs of publication of this article were defrayed, in part, by the payment of page
charges. This article must, therefore, be hereby marked “advertisement” in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
Faculty of Medicine, Division of Cardiology, McGill University, Montreal, Canada.
Address correspondence to Shirya Rashid, Department of Medicine, Division of Cardiology,
McGill University, Royal Victoria Hospital, Room H7–13, 687 Pine Avenue West, Mon-
treal, Quebec, Canada H3A 1A1.
E-mail: shirya2004@yahoo.ca
Copyright © 2007 NAASO
lipid transfer to HDL by lipoprotein lipase and reduced
HDL clearance by hepatic triglyceride lipase as a result of
endurance training are two important mechanisms for in-
creases in HDL observed from exercise.
Key words: adiposity, high-density lipoproteins, diet,
exercise, cardiovascular risk
Introduction
The strong inverse relationship between plasma concen-
trations of high-density lipoprotein (HDL)1-cholesterol and
the risk of developing coronary artery disease (CAD) (1)
has stimulated interest in determining the mechanisms and
optimal management of low HDL-cholesterol (⬍35 mg/dL)
(2,3). A number of genetic, lifestyle, and environmental
factors have been shown to contribute to the lowering of
HDL-cholesterol. Genetic disorders characterized by low
HDL-cholesterol concentrations are rare and include
mutations in apolipoprotein A-I (4 – 6), the major protein
component of HDL, defects in HDL-mediated efflux of
cholesterol from peripheral cells through the membrane
transporter ABCA1 (7–9), and hypercatabolism of normal
apolipoprotein A-I (10). In contrast, lifestyle factors—
including obesity, physical inactivity, diet, smoking, and
advanced alcohol-related liver disease—account for the
majority of cases of low HDL-cholesterol levels (11–13).
In particular, obesity, defined as the excessive accumu-
lation of body fat, is frequently associated with a low
concentration, adverse distribution pattern, and abnormal
metabolism of HDL particles (14,15). Obesity is a highly
prevalent chronic state observed in 32% of all adults in the
United States (16). Moreover, the Framingham Heart Study
(17) and the Third National Health and Nutrition Examina-
tion Survey (18) have shown a significant increase in life-
time risk of CAD with level of obesity, which may be partly
attributed to its association with low HDL-cholesterol lev-
1
Nonstandard abbreviations: HDL, high-density lipoprotein; CAD, coronary artery disease;
LDL, low-density lipoprotein; VAT, visceral adipose tissue; VLDL, very-low-density li-
poprotein; LCAT, lecithin cholesterol ester transfer protein; CETP, cholesteryl ester transfer
protein; FFA, free fatty acid; HSL, hormone-sensitive lipase; PLPT, phospholipid transfer
protein; apo A-I, apolipoprotein A-I.
OBESITY Vol. 15 No. 12 December 2007 2875
Obesity and High-density Lipoproteins, Rashid and Genest
els. Conversely, an increase in HDL-cholesterol levels has
been proven to be cardioprotective, such that each 1-mg/dL
elevation in HDL reduces CAD risk by 2% to 3%, indepen-
dently of the levels of low-density lipoprotein and triglyc-
erides (19). A comprehensive pathophysiological explana-
tion for the association between obesity and increased CAD
risk is still lacking. However, because the variation in
HDL-cholesterol levels is an important modifiable CAD
risk factor in obese states, it is imperative to elucidate the
mechanisms which contribute to the lowering of HDL-
cholesterol in obesity and to determine the efficacy of
treatments aimed at raising HDL-cholesterol levels in obese
individuals.
This paper will outline the evidence linking obesity to
variations in HDL-cholesterol metabolism, characterize the
pathophysiologic mechanisms responsible, and examine the
efficacy of weight loss achieved with exercise—the recom-
mended non-pharmacologic intervention for increasing
HDL-cholesterol levels in obese individuals— on poten-
tially reversing these changes.
Evidence that Adiposity Is Associated with
Reduced HDL-cholesterol Levels
Several indices of adiposity have been used to show an
association between obesity and HDL-cholesterol. Epide-
miologic data from the large, cross-sectional multinational
Lipid Research Clinics Program Prevalence Study found a
significant inverse correlation between the Quetelet index of
body mass (height divided by weight squared) and total
HDL-cholesterol in adults of both sexes (20). The associa-
tion between the Quetelet index and HDL-cholesterol re-
mained significant when multivariate analysis was applied
to control for some confounding variables affecting HDL-
cholesterol (smoking, alcohol intake, exogenous steroid
hormone use, and plasma triglyceride levels), although oth-
ers were not considered (diet, habitual exercise patterns). To
quantify the association, covariance-adjusted mean HDL-
cholesterol levels were calculated at the 10th and 90th
percentiles for Quetelet index and revealed that mean HDL-
cholesterol levels were 6 to 7 mg/dL higher at the Quetelet
90th percentile than at the 10th percentile. This difference in
HDL-cholesterol levels has been reported to significantly
alter the risk of mortality from CAD (1).
BMI, expressed as body weight in kilograms divided by
height in square meters, is frequently used as a measure of
body fatness in large epidemiologic studies (21). The World
Health Organization (2002) delineates individuals with a
BMI ⱖ25 kg/m2 and ⱕ29.9 kg/m2 as overweight and those
with a BMI ⱖ30 kg/m2 as obese. In one large-scale study
(1566 men and 1627 women) of participants from the Fra-
mingham Offspring Study, lipoprotein and BMI measures
were taken to determine the effects of BMI on coronary risk
factors. Plasma HDL-cholesterol and apolipoprotein A-1
2876 OBESITY Vol. 15 No. 12 December 2007
levels both significantly declined in a linear fashion with
increasing BMI (ranging from ⬍21 to ⱖ30 kg/m2) (21). An
increase in BMI, moreover, was strongly and significantly
related to reduced HDL levels and was more strongly re-
lated to reduced HDL than other cardiovascular risk factors,
such as low-density lipoprotein (LDL)-cholesterol levels (21).
Although the Quetelet index and BMI have been used as
a measure of adiposity in many epidemiologic studies
(17,22), they are indirect indices of obesity, measuring both
lean and adipose tissue mass, and they do not provide
information on the distribution of body fat (23). This is
particularly of concern in women, because compared with
men, the prevalence of complications in lipid metabolism
and other cardiovascular disease risk factors is less consis-
tently correlated with the degree of obesity in women.
Instead, the distribution of body fat in women (and men) is
an independent predictor of the adverse metabolic patterns
of obesity, cardiovascular morbidity, and mortality (23,24).
More specifically, studies that have examined regional fat
distribution, using both indirect anthropometric parameters
(waist-to-hip circumference, subcutaneous skinfold thickness)
(25) and direct measurement of adipose tissue surface areas
(computed tomography) (23), have shown a close correlation
between intra-abdominal fat deposition and indices of car-
diovascular risk, including a low HDL-cholesterol/total cho-
lesterol ratio, hypertension, glucose intolerance, hypertri-
glyceridemia, and hyperinsulinemia (23,25,26). Such an
accumulation of intra-abdominal visceral fat is more charac-
teristic of men, who generally exhibit android or upper body
obesity, than of women, who more typically exhibit gynoid or
lower body obesity, and explains the greater correlation of total
fat distribution to an abnormal metabolic profile in men (27).
Peiris et al. (23) quantified the effect of regional fat
deposition on HDL levels in healthy premenopausal women
with a wide range of body weight and adiposity and found
(using computed tomography) that 15% of the variance in
the HDL-cholesterol/total cholesterol ratio was explained
by variations in visceral fat mass. However, despite the
significant effect of adipose tissue distribution on variations
in HDL-cholesterol levels, body fat distribution per se has
been found to be insufficient to explain observed associa-
tions between visceral intra-abdominal adipose tissue and
HDL-cholesterol alterations in premenopausal women. De-
spres et al. (15) showed that obesity is a necessary condition
for the association in premenopausal women. In a sample of
22 lean women with a mean BMI of 21 kg/m2, they found
no significant correlation between waist-to-hip ratio and
plasma HDL levels, whereas computer tomography-mea-
sured high trunk abdominal fat and abdominal cell hyper-
trophy correlated negatively with plasma HDL apoliprotein
A-I (the major protein component of HDL particles) and
HDL2 subfraction cholesterol levels (r ⫽ ⫺0.51 and p ⬍
0.05 for both).
Obesity and High-density Lipoproteins, Rashid and Genest
In postmenopausal women, in contrast, it seems that
obesity is not required to be present for correlations between
intra-abdominal fat and HDL levels. Ostlund et al. (25)
determined that variations in abdominal adiposity, as as-
sessed through the waist-to-hip ratio, explained 32% of the
variance of HDL2-cholesterol in healthy, non-obese (or
mildly obese) elderly (60 to 70 years of age) men and
women (independently of sex). It has been found both in
perimenopausal and postmenopausal obese women that a
high visceral adipose tissue (VAT) area, as assessed with
computer tomography, is associated with low HDL concen-
trations (28). Women with VAT of 106 to 162 cm2 are 2.5
times more likely to have low HDL-cholesterol levels, and
women with a VAT of ⱖ163 cm2 are 5.5 times more likely
to have low HDL-cholesterol, than women with a VAT of
105 cm2 or less (28). Thus, the appropriate index of adi-
posity to apply in studies investigating associations between
adiposity and plasma HDL-cholesterol concentrations is
dependent on the age, metabolic state, and sex of the par-
ticular subpopulation/sample group under study.
Studies have additionally examined the impact of ethnic-
ity on HDL levels and whether adiposity contributes to the
relationship. For example, compared with white individuals,
black individuals have consistently been characterized by
higher plasma HDL-cholesterol concentrations. In one
study, metabolic risk variables, including plasma HDL-
cholesterol levels, along with body fatness and VAT accu-
mulation, were measured in healthy white men and women
and black (African-American) men and women in North
America (29). Plasma HDL-cholesterol levels were found to
be higher in black men and women than in their white
counterparts (29). This elevation in HDL-cholesterol levels
could not be explained by the extent of subcutaneous fat or
total body fat mass in the black individuals vs. the white
individuals, because no race differences were found in these
variables (29). However, a lower accumulation of VAT in
blacks vs. whites accompanied their higher plasma HDL-
cholesterol levels and, indeed, could explain, at least in part,
their elevated HDL-cholesterol levels (29). In contrast, eth-
nicity per se provided only a minor contribution to the
variance in plasma HDL-cholesterol levels (29).
Although in the case of black individuals, compared with
white individuals, differences in adiposity contribute to
differences in HDL-cholesterol levels, this is not always the
case when comparing different ethnic groups. In another
study, healthy men and women of European and South
Asian descent in North America were assessed for their
anthropometric variables and lipid levels (30). Although
BMI and waist circumference were similar between Euro-
pean and South Asian men and European and South Asian
women, South Asian men and women had significantly
lower HDL-cholesterol values compared with their Euro-
pean counterparts (30). In this case, ethnicity was an inde-
pendent predictor of HDL-cholesterol levels after adjusting
for BMI and waist circumference, independently of age and
height (30).
To our knowledge, no epidemiologic or clinical study to
date has established a causal link between the low plasma
HDL-cholesterol concentrations observed in obese states
and an increased risk for development of CAD events. Other
lipoprotein abnormalities, such as increases in the athero-
genic very-low-density lipoproteins (VLDLs) and LDLs,
and other metabolic alterations, such as glucose intolerance
and insulin resistance, are also associated with obesity and
likely contribute to the increased CAD risk in obesity. These
changes, however, seem to occur less consistently than low
HDL-cholesterol levels in obesity. Moreover, the knowl-
edge that HDL-cholesterol levels are an important marker of
CAD risk and the finding that low HDL-cholesterol levels
are consistently associated with several indices of adiposity
have stimulated research on the mechanisms of HDL low-
ering in obese states. These mechanisms will be reviewed in
the next section.
Mechanisms of HDL Lowering in Obesity:
Effect of Obesity on HDL Subfractions
In addition to the levels of HDL, the distribution and
composition of HDL subfractions determine their functional
effectiveness. HDL particles are a discrete but highly het-
erogeneous group of lipoproteins that differ in density, size,
lipid content, and protein composition (31). Not surpris-
ingly, obesity has been shown to adversely affect the levels
of HDL subfractions principally associated with cardiopro-
tection: HDL2, apolipoprotein A-I, and pre-␤1. This section
will examine the mechanisms by which obesity is reported
to mediate variations in HDL subfractions and their impli-
cations.
Effect of Obesity on HDL2 Levels
There are several classification systems that have been
used to characterize HDL subpopulations. Early studies on
the effect of obesity on HDL subfractions used the tradi-
tional sequential ultracentrifugation and precipitation tech-
niques to separate HDL into its two principle subfractions:
the less dense, cholesterol- and phospholipid-enriched
HDL2 particles and the denser, smaller, and relatively pro-
tein rich HDL3 fraction (2). HDL2 particles are generated
from HDL3 particles when triglyceride-rich lipoproteins are
hydrolyzed by lipoprotein lipase and subsequently transfer
their surface components (including cholesterol and phos-
pholipid) to HDL3 (2). HDL2 particles are also formed from
smaller HDL particles when lecithin cholesterol ester trans-
fer protein (LCAT) esterifies cholesterol within HDL (32).
Conversely, the smaller, denser HDL3 subfraction is formed
when HDL2 particles are hydrolyzed by the enzyme hepatic
lipase.
OBESITY Vol. 15 No. 12 December 2007 2877
Obesity and High-density Lipoproteins, Rashid and Genest
Because of the significant cardioprotective role of HDL2,
the concentrations of HDL2-cholesterol and its relationship
to obesity were studied in a number of different sample
population groups. In one study comparing HDL concen-
trations in 68 age-matched obese (mean BMI ⫽ 32 ⫾ 4
kg/m2) and control subjects, cholesterol and protein con-
tents of HDL2 were found to be 50% lower in the obese
subjects (33). In addition, there was a greater negative
correlation between BMI and HDL2 than between BMI and
HDL3 levels. It was believed that the reduced HDL2 levels
in the obese subjects were caused by two factors: an overall
elevation in very-low-density triglycerides and a slight in-
crease in glycemia, reflecting insulin resistance (33). These
factors may have contributed to decreased lipolysis and a
defective transfer of surface elements to HDL3 in the obese
subjects (33).
Other studies conducted in obese premenopausal women
(26) and older adults of both sexes of varying adiposity (25)
were designed to investigate the importance of adipose
tissue distribution on HDL2-cholesterol levels. These stud-
ies showed in their respective sample populations that intra-
abdominal fat was a more important independent predictor
of low HDL2-cholesterol levels than mid-thigh fat (26),
BMI, or total percentage body fat (25).
In another study, examining the contribution of intra-
abdominal fat to sex differences in hepatic lipase activity
and HDL heterogeneity, it was determined that intra-ab-
dominal fat is a major determinant of the sex differences in
hepatic lipase activity (34). Men have significantly more
intra-abdominal fat and a higher hepatic lipase activity and
those result in lower HDL2 levels in men (34).
Data from several cross-sectional studies conducted
among survivors of myocardial infarction and among pa-
tients with angiographically-measured atherosclerosis (35)
indicated that levels of both HDL2 and HDL3 subfractions
were significantly lower in these subjects than in healthy
control subjects. However, the differences were greater for
HDL2 and especially for the relatively rich, large HDL2
species, HDL2b. Other studies have determined that HDL2 is
the most reliable and sensitive predictor of a normolipi-
demic individual’s ability to clear atherogenic triglyceride-
rich lipoproteins from plasma postprandially (36). These
studies suggest, but do not prove, that HDL2 vs. HDL3
levels are more closely associated with protection against
CAD. Conversely, they suggest that the reduction in HDL2
levels in obese states may be associated with increased risk
of CAD events.
The possible mechanisms by which obesity promotes
reduced HDL2-cholesterol levels may be divided into indi-
rect and direct processes. First, other metabolic abnor-
malities present in obese states may indirectly cause the
lowering of HDL2 levels in obese individuals. Hyper-
triglyceridemia, in particular, is frequently associated with
reduced HDL levels and enhanced HDL catabolism in obese
2878 OBESITY Vol. 15 No. 12 December 2007
Figure 1: CETP mediates the transfer of triglycerides from the
triglyceride-rich lipoproteins— chylomicrons and VLDLs—to
HDLs. CETP also mediates the reverse transfer of cholesteryl ester
from the core of HDL particles to VLDLs and chylomicrons. The
net result is the formation of large, triglyceride-rich, cholesterol
ester core– depleted HDL particles, which are an ideal substrate for
hepatic lipase, that are cleared by the liver.
subjects (37). In hypertriglyceridemic states, such as obe-
sity, the plasma protein, cholesteryl ester transfer protein
(CETP), mediates a greater net transfer of triglycerides
from the triglyceride-rich lipoproteins (VLDLs and chylo-
microns) to HDL particles than normal (38,39) (Figure 1).
This has been shown to produce triglyceride-rich HDL
particles, including HDL2 particles (38). Triglyceride-rich
HDL particles are also formed from a greater pool of VLDL
particles in hypertriglyceridemic, insulin-resistant states. In
some cases of hypertriglyceridemia, insulin resistance is
present, and this insulin resistance then drives the release of
free fatty acids (FFAs) from adipose tissue to the circulation
(40). This feed-forward cycle of FFA release into the cir-
culation is mediated by the enzyme hormone-sensitive
lipase (HSL) (41,42). HAL activity is normally suppressed
by insulin after a meal (41,42). However, the activity of this
lipase is enhanced in insulin-resistant states, such as obesity,
driving the release of FFAs into the circulation (41,42). The
FFAs provide the substrate for the formation of VLDL
particles by the liver (40). The result is a greater mass of
VLDL particles in the circulation from which a greater
amount of triglycerides are transferred to HDL particles,
causing the HDL particles to be triglyceride rich (40).
Triglyceride-rich, large HDL2 particles are the preferred
substrate for the enzyme hepatic lipase, which hydrolyzes
HDL and promotes hepatic HDL uptake (38,43). Because
obese subjects have been found to have significantly in-
creased protein mass and activities of CETP and post-
heparin hepatic lipase (44), triglyceride enrichment of
HDL2 by CETP and VLDL and its subsequent hydrolysis by
Obesity and High-density Lipoproteins, Rashid and Genest
hepatic lipase may be a potential mechanism by which
HDL2 levels are indirectly reduced in obese hypertriglycer-
idemic individuals.
Plasma triglyceride levels, however, vary greatly in obese
individuals, and a large proportion of obese individuals are
not hypertriglyceridemic (45). Moreover, significant in-
creases in HDL concentration have been shown in severely
obese men and women after weight loss through dieting and
exercise, despite the lack of change in plasma triglyceride
levels (46). Therefore, alternate mechanisms likely play a
role in mediating reduced HDL2 levels in obese subjects.
Because increased CETP mass and activity levels, which
can potentially decrease HDL2 levels (as mentioned above),
have been identified in obese states (44), pharmacologic
inhibition of CETP with CETP inhibitors, such as the re-
cently characterized torcetrapib series of CETP inhibitors
(47,48), could potentially benefit obese individuals with low
HDL2 levels. In healthy individuals, CETP mass does not
correlate with HDL2 (49) or total HDL (50) levels, unless
the individuals are also hypertriglyceridemic (50) or insulin
resistant (51). Thus, CETP inhibition could potentially ben-
efit HDL metabolism in obese individuals more than in
normal, healthy individuals.
It should be noted that a large Phase III clinical trial
testing the safety and efficacy of torcetrapib was recently
halted because of the higher mortality rates detected in
post-cardiac event patients using torcetrapib (52,53). Thus,
torcetrapib, designed as a novel drug therapy aimed at
raising HDL-cholesterol and reducing atherosclerosis and
cardiac events, has been deemed a failure. Its failure shows
that factors other than total HDL-cholesterol levels are
important to assess when evaluating pharmacologic ap-
proaches to raising HDL-cholesterol in obese patients (53).
These factors include HDL particle size and composition
(53). Moreover, the appropriate clinical endpoints in deter-
mining the efficacy of pharmaceutical approaches to raising
HDL in obese (and non-obese) patients are decreasing ath-
erosclerosis and decreasing the vulnerability of atheroscle-
rotic plaques to rupture (53).
Despite the failure of torcetrapib, decreasing CETP-
mediated transfer of cholesteryl ester from HDL still seems
to be a sound strategy for increasing HDL levels and low-
ering CAD risk (53,54) in obese (and non-obese) subjects.
However, drugs that modify HDL structure in a different
manner than torcetrapib are likely required (53). The design
of such drugs will be greatly aided by the newly character-
ized crystal structure of CETP (53,55).
The role in humans of endothelial lipase, a lipase shown
to mediate a decrease in HDL levels in animal models, has
also been studied. Endothelial lipase has been shown to
hydrolyze phospholipids on the surface of HDL particles
containing either apo A-I only or both apo A-I and apo A-II
together (56). The result is a decrease in particle size with
no dissociation of the apolipoproteins (56). Studies showed
an elevation in endothelial lipase with increasing visceral
adiposity but no correlation between endothelial lipase and
either total HDL- or HDL2-cholesterol levels (57). Thus,
endothelial lipase was found not to mediate the decrease in
HDL2 levels seen in obesity (57).
The expression levels of another recently discovered
lipase has been studied in the context of obesity. The lipase
—adipose triglyceride lipase—mediates the hydrolysis of
triglyceride stores in adipocytes to form FFAs, which are
released into the circulation (58,59). Adipose triglyceride
lipase, together with HSL, is important for the hydrolysis of
triglycerides in adipose tissue in basal conditions (60).
In a recent study, adipose tissue biopsies were taken from
obese subjects with a wide range of insulin resistance to
assess mRNA and protein levels of adipocyte triglyceride
lipase (61). There were strong associations, independent of
fat mass, between insulin resistance and hyperinsulin-
emia and the mRNA and protein of adipocyte triglyceride
lipase (61). Overall, mRNA and protein levels of adipocyte
triglyceride lipase were found to be reduced in insulin-
resistant compared with insulin-sensitive subjects (61).
These results suggest that in insulin-resistant, obese
states, decreased expression of adipose triglyceride lipase
decreases the mobility of FFAs from their triglyceride stores
in adipocytes. This indicates less FFA flux from adipocytes
to the liver. Therefore, less FFA substrate would be avail-
able for VLDL production in the liver. With less VLDL
produced, there would be less transfer of triglycerides from
VLDL to HDL (including HDL2 particles) that would make
the HDL particles triglyceride-rich and unstable after action
by hepatic lipase. Thus, decreased expression of adipose
triglyceride lipase in obese, insulin-resistant states cannot
account for reduced HDL (and HDL2) levels in these states.
The role of the protein phospholipid transfer protein
(PLTP) has also been studied in terms of its effect on
remodeling HDL particles and its activity in obese states.
PLTP has been found in vitro to remodel HDL3 particles
(particle diameter, 8.7 nm) into two distinct populations of
HDL— one larger, of particle diameter 10.9 nm, and one
smaller, of particle diameter 7.8 nm (62). PLTP has also
been shown to alter HDL2 particles in vitro such that a
population of pre-␤-like HDL particles are produced (63).
PLTP activity was found to be elevated in a group of 8
healthy obese men (BMI ⬎ 27 kg/m2), relative to 24 non-
obese individuals (64) (Figure 2). PLTP activity, moreover,
was positively related to BMI and waist-to-hip circumfer-
ence ratio (64). Conversely, weight loss with gastric bypass
surgery in severely obese middle-age women resulted in a
significant decrease in PLTP activity and, concomitantly, an
increase in the size of HDL2 particles (65). Thus, a reduc-
tion in PLTP activity with weight loss reversed the athero-
genic small, dense HDL particles seen in obese individuals
(65).
OBESITY Vol. 15 No. 12 December 2007 2879
Obesity and High-density Lipoproteins, Rashid and Genest
Figure 2: PLTP mediates the transfer of phospholipids to HDL
particles. PLTP action results in the formation of larger and
smaller HDL particles, along with the formation of pre-␤-HDL
particles, which are cleared by the kidneys.
A number of studies have suggested that obesity per se
directly induces a reduction in HDL-cholesterol levels. The
factors responsible for the well-characterized exercise-
mediated rise in HDL-cholesterol levels were examined by
Williams et al. (66). Post hoc and regression analysis of 64
middle-age men who had completed either a controlled
moderate exercise training program for 1 year or maintained
a sedentary lifestyle revealed that the majority of plasma
HDL2-cholesterol increase induced by moderate exercise
was caused by a change in body weight. Similarly, Wolf and
Grundy (67) found that caloric restriction did not induce a
rise in HDL-cholesterol levels in obese patients until after
most of their excess adipose tissue had been removed.
These clinical studies are consistent with in vitro evi-
dence that adipose tissue can specifically bind to and me-
diate the uptake of 125I-HDL2 and HDL3 (68,69). The
uptake of HDL2 by adipose tissue may be characterized as
being tissue specific, because abdominal subcutaneous adi-
pocytes mediate a greater uptake and binding than omental
adipocytes (68,69). Also, HDL2 uptake by adipocytes is
dependent on fat cell size, with hypertrophied cells display-
ing greater uptake (69).
Overall, both direct and indirect mechanisms related to
the metabolic consequences of obesity may account for
reduced HDL2 levels in obese subjects. The relative impor-
tance of each seems to be dependent on the primary meta-
bolic abnormality present and the extent and distribution of
adiposity in the individual.
2880 OBESITY Vol. 15 No. 12 December 2007
Effect of Obesity on Apolipoprotein A-I Levels
The HDL2 subfraction contains a relatively high concen-
tration of apolipoprotein A-I (apo A-I) (70), the major
protein component of HDL contributing to ⬃50% of its
mass (39) and an important determinant of its structure and
number in the circulation. Apo A-I is a key marker of
HDL-cholesterol levels, and studies have shown that the
level of apo A-I is more closely correlated with the reduced
risk of atherosclerosis than other markers of HDL-choles-
terol (71,72).
As with levels of HDL2, apo A-I levels are frequently low
in obese patients. Obesity was shown to be associated with
reduced plasma HDL apo A-I levels in the Framingham
Offspring Study conducted in 4260 young adult men and
women (73). Both in vitro (74,75) and in vivo studies in
transgenic animals (76) have suggested that apo A-I directly
protects against the development of atherogenesis by either
preventing the oxidation or self-aggregation of proathero-
genic LDL particles within the arterial wall (75) or by
stimulating the mobilization of cholesterol from the arterial
wall (74). Therefore, the reduced apo A-I levels associated
with obesity may contribute to the increased risk of CAD in
obese subjects.
Brinton et al. (77), Gylling et al. (78), and Ooi et al. (79)
studied the factors responsible for low plasma HDL apo A-I
concentrations in obese subjects, using a kinetic approach.
More specifically, in their studies, radioisotopes were used
to trace the kinetic behavior of apo A-I in a group of
normolipidemic, non-smoking obese individuals (mean
BMI ⫽ 30 kg/m2). Both the rate of input of apo A-I into
plasma and the time that apo A-I resides in plasma have
been shown to influence apo A-I concentrations under dif-
ferent metabolic conditions (80,81). In obese subjects, two
of the above investigators (77,78) found that a reduction in
the residence time of apo A-I in plasma—a 30% reduction
vs. control subjects—was the principle cause of low apo A-I
levels. Conversely, the input rates of apo A-I were not
different between obese subjects and non-obese normolipi-
demic, control subjects. Ooi et al. found that both the
fractional catabolic rate and production rate of apo A-I are
elevated in obese individuals compared with lean controls
(79).
Together, these studies suggest that the obese state di-
rectly enhances the rate of clearance and can enhance the
secretion rate of HDL (measured as apo A-I) into plasma.
This was confirmed by a later study in which the level of
intra-abdominal fat, as measured by magnetic resonance
imaging, strongly correlated with the clearance rate of HDL
apo A-I (r ⫽ 0.98, p ⫽ 0.003) (82). It is possible that the
increased plasma clearance rate of apo A-I in obese subjects
contributes to the increased risk of CAD in obesity.
The enhancement in HDL catabolism in obese states may
be attributed to enhanced hepatic lipase and CETP activity
levels in obesity. First, it is well established that hepatic
Obesity and High-density Lipoproteins, Rashid and Genest
lipase activity levels increase in obese states (83,84). High
hepatic lipase activity is associated with reduced levels of
HDL2 (84). Hepatic lipase may mediate this effect on HDL2
levels by hydrolyzing the surface triglycerides on HDL
particles, rendering the particles less stable, thus enhancing
the clearance of HDL from the circulation (85). Further-
more, CETP may also play a role in the enhanced clearance
of HDL in obese states. CETP activity has been found to
increase significantly in obese subjects relative to control
subjects (83). Moreover, CETP activity, independent of
post-heparin hepatic lipase and lipoprotein lipase activities,
has been found to correlate negatively with HDL-choles-
terol levels (44). CETP acts to transfer triglycerides from
triglyceride-rich VLDL particles and chylomicrons to HDL
particles and also mediates the reverse transfer of cho-
lesteryl ester from HDL to VLDL and chylomicrons (86).
This results in triglyceride-rich HDL particles that are de-
pleted of core cholesteryl ester, directly resulting in reduced
HDL-cholesterol levels (86). Triglyceride-rich HDL parti-
cles produced through CETP action are also a good sub-
strate for hepatic lipase, the action of which enhances the
clearance of HDL particles (86).
Effect of Obesity on Pre-␤1 Levels
Reduced HDL2 cholesterol and apo A-I levels have been
widely identified as independent CAD risk factors in obe-
sity. More recently, however, a deficiency in another HDL
subfraction—pre-␤-HDL— has been identified in obese
states. Pre-␤-HDL is more closely linked to the primary
anti-atherosclerotic function of HDL, which is mediating
reverse cholesterol transport. Reverse cholesterol transport
is the process by which cholesterol in peripheral (non-
hepatic) tissues is transported to the liver for re-use or bile
acid synthesis (39). In this reverse cholesterol transport
system, the pre-␤-HDL subfraction is believed to promote
the efflux of cholesterol from peripheral cells (the first step
in reverse cholesterol transport) (87) and may, conse-
quently, prevent the accumulation of cholesterol, foam
cells, and fatty lesions in cells of the arterial intima.
Pre-␤-HDL species are effectively isolated by two-
dimensional non-denaturing electrophoresis of apoA-I-
containing HDL (87– 89). Kinetic and pulse-chase experi-
ments conducted in fibroblasts radiolabeled with cholesterol
and plasma suggest that three different pre-␤-HDL subspe-
cies are involved in the transport of cell-derived cholesterol
in plasma (90,91). In this model, pre-␤1-HDLs are the initial
mediators of cholesterol efflux from peripheral cells. Sub-
sequently, they uni-directionally transfer their cholesterol
through CETP to larger pre-␤2-HDLs, and then pre-␤3-
HDLs, and finally to ␣-HDL (identical to HDL2), where the
cholesterol is esterified by LCAT.
Pre-␤ LpAI is a partially lipidated single apo A-I moiety
with unknown function (88). It is likely a thermodynami-
cally unstable transition form between lipid-free apo A-I
and an organized, i.e., thermostable, particle with two apo
A-I molecules and a phospholipid disk (88). The major
acceptors of cellular cholesterol are lipid-free apo A-I and
nascent ␣-LpAI (88).
Sasahara et al. (87) found that the distribution of ␣-HDL
and ␤-HDL particles was shifted to smaller species in obese
subjects (23 middle-age men and postmenopausal women
with a BMI between 25 and 36 kg/m2) compared with lean
subjects (BMI ⬍ 25 kg/m2). Total HDL-cholesterol, HDL
apo A-I, and ␣1-HDL levels were significantly reduced in
obese subjects, confirming earlier studies. However, the
demonstration of increased pre-␤1-HDL in obese subjects
was a novel finding. Furthermore, on both univariate and
stepwise regression analysis, BMI was directly correlated
with pre-␤1-HDL and inversely with ␣1-HDL.
Possible causes of raised pre-␤1-HDL levels in obesity
are greater hepatic lipase and CETP activities found in
obese individuals in comparison with lean controls (44).
The origins of pre-␤-HDL provide insight into the impli-
cations of such raised hepatic lipase and CETP activities
in obesity. Pre-␤1-HDL are discoidal nascent HDL par-
ticles that are generated partly from excess surface lipid
and apoA-I components of HDL2 when HDL2 is catabo-
lized. This process occurs when HDL2 transfers cholesteryl
esters to triglyceride-rich lipoproteins through the action of
CETP or is hydrolyzed through the action of hepatic lipase
(Figure 2). Thus, increased CETP and hepatic lipase activ-
ities in obese individuals would tend to reduce ␣1- and
increase ␤1-HDL levels.
In addition, PLTP likely has a role in the generation of
pre-␤1 particles in obese individuals. PLTP mediates an
increase in phospholipids onto the surface of HDL particles,
resulting in a displacement of apo A-I and the generation of
new pre-␤1 particles (92) (Figure 2). In humans with a wide
range of BMI (19 to 43 kg/m2), PLTP activity was shown to
be associated with BMI, body fat mass, and subcutaneous
fat area (92). Overall, PLTP activity was significantly
higher in obese vs. non-obese individuals (92). Moreover, in
linear regression analysis, BMI was the sole predictor of
plasma PLTP activity (92).
Interestingly, there was also a reduction in the pre-␤1-
HDL-to-pre-␤2-HDL ratio in obese subjects in the above
study, suggesting an inhibition in the conversion of pre-␤1
to pre-␤2 (87). This may reflect a disruption in reverse
cholesterol transport along the HDL particle subfractions
(87). Indeed, in a later in vitro cell culture study by Sasahara
et al. (93), obese individuals showed an overall decrease in
the capacity of HDL subfractions to promote cholesterol
efflux from fibroblasts. Compared with lean subjects, the
cholesterol efflux activity of pre-␤1-HDL was higher and
that of pre-␤2-HDL was lower in obese individuals. This is
consistent with a disturbance in the sequential transfer of
cholesterol from peripheral cells to HDL subfractions in
reverse cholesterol transport. Furthermore, because pre-␤1-
OBESITY Vol. 15 No. 12 December 2007 2881
Obesity and High-density Lipoproteins, Rashid and Genest
HDL concentrations are increased in both obesity and CAD
(94), it may be a link between obesity, lowered reverse
cholesterol transport, and increased risk of CAD in obese
states.
Effect of Weight Loss on Plasma
HDL-cholesterol
In the above sections, we established 1) that the levels of
HDL-cholesterol and composition of HDL particles are
adversely altered in obese individuals; 2) that the extent of
the variation is determined by the regional distribution of fat
and specific population under study; and 3) that the alter-
ations in HDL can lead to a reduction in the cardioprotective
functions of HDL. This section will focus mainly on the
mechanisms and efficacy of weight loss achieved non-
pharmacologically through exercise in raising HDL-choles-
terol levels in overweight individuals.
As a brief explanation of the pharmacologic weight loss
options, orlistat, sibutramine, and rimonabant are three ma-
jor current weight loss medications (95). Orlistat is a gastric
and pancreatic lipase inhibitor (95). It reduces dietary fat
absorption by ⬃30% (96) and results in a mean weight loss
of 3 kg (95). In a meta-analysis of 11 placebo-controlled
trials of 1 year, orlistat use has been shown to reduce blood
pressure, LDL-cholesterol, and fasting glucose in patients
with diabetes (97,98). However, there are no long-term
outcome data showing that orlistat use decreases major
obesity-related morbidity and mortality (95).
Sibutramine is a combined serotonin and noradrenaline
reuptake inhibitor, which works primarily through its active
amine metabolites (99). Sibutramine produces a mean
weight loss of 4 to 5 kg (95), which is achieved predomi-
nantly by its centrally mediated action in increasing satiety,
thereby reducing food intake (95,99). It also enhances en-
ergy expenditure by stimulating thermogenesis—that is, it
increases sympathetic activity to thermogenically active
brown fat (95,99). This peripheral action of sibutramine,
however, plays a minor part in weight reduction (95). Long-
term studies have not shown any significant effect of sib-
utramine on LDL-cholesterol and glycemic control (95).
Similar to orlistat, there is a lack of long-term data on the
effect of sibutramine on major obesity-related morbidity
and mortality (95). There is, however, a current clinical trial
called the Sibutramine Cardiovascular Outcomes Trial,
which is assessing the efficacy of sibutramine in reducing
cardiac events such as myocardial infarction, stroke, and
cardiovascular mortality in 9000 obese and overweight pa-
tients (95). The Sibutramine Cardiovascular Outcomes Trial
is expected to finish in 2008 (95).
Neither orlistat nor sibutramine produces a consistent
increase in HDL-cholesterol levels (95). In contrast, rimon-
abant, an endocannabinoid receptor antagonist, which re-
duces weight by 4 to 5 kg, on average, and decreases waist
2882 OBESITY Vol. 15 No. 12 December 2007
circumference, has been found in major clinical trials (95) to
consistently increase HDL-cholesterol concentrations, when
given at a dose of 20 mg/d. Rimonabant’s action in reducing
food intake seems to be both centrally and peripherally
mediated (95). The peripheral action is potentially through
enhanced thermogenesis through increased oxygen con-
sumption in skeletal muscle and reduced hepatic and adi-
pocyte lipogenesis, among a variety of other mechanisms.
In the Rimonabant In Obesity–North America multi-center,
randomized, double blind trial of more than 3000 obese or
overweight individuals (BMI ⱖ 30 kg/m2 and BMI ⱖ 27
kg/m2, respectively), patients were randomized to be on a
diet (600 kcal/d deficit) and receive placebo, 5 mg/d rimon-
abant, or 20 mg/d rimonabant (100). After 1 year, the group
receiving 20 mg/d rimonabant achieved greater mean reduc-
tions in weight and waist circumference and a greater in-
crease in HDL-cholesterol than the placebo group (100). It
has been estimated that ⬃47% to 58% of the improvement
in HDL-cholesterol mediated by rimonabant is beyond that
expected through weight loss alone and may be mediated by
a direct effect of rimonabant on peripheral tissues, such as
the liver (101). Rimonabant has not been found to alter
LDL-cholesterol or blood pressure consistently, and there
are currently no data on cardiovascular morbidity or mor-
tality (95). However, several trials are underway, the largest
of which is the Comprehensive Rimonabant Evaluation
Study of Cardiovascular Endpoints and Outcomes trial (95).
This trial is studying the effect of rimonabant on myocardial
infarction, stroke, and cardiovascular death in 17,000 obese
patients (95).
Efficacy of Exercise Compared with Dieting in Raising
HDL-cholesterol in Overweight Individuals
The two recommended non-pharmacologic approaches to
raising plasma HDL-cholesterol in overweight individuals
are exercise and diet. In two prospective studies, reductions
in energy intake to 1000 kcal/d produced modest weight
loss in patients of varying degrees of obesity (102,103). In
both studies, after sustained weight loss and a stable reduc-
tion in body weight, the total HDL-cholesterol levels in-
creased above baseline values. Similarly, in a study in
severely obese individuals, both low-carbohydrate and con-
ventional diets (with caloric restrictions imposed in both)
produced similar (non-significant) increases in HDL-cho-
lesterol above baseline (104).
Although in one random, controlled, prospective study,
weight loss achieved through long-term calorie restriction
was equally effective as exercise in raising total HDL-
cholesterol levels in overweight individuals (105), dieting in
general has been shown to be less effective in altering HDL
levels than exercise. In obese male subjects, hypocaloric
dieting, in contrast to aerobic exercise (70), did not increase
the cardioprotective HDL2 and apo A-I subfractions and
actually diminished the effects of weight loss on increasing
Obesity and High-density Lipoproteins, Rashid and Genest
HDL2 levels (106). Also, weight loss achieved through the
National Cholesterol Education Program’s recommended
low-saturated-fat, low-cholesterol diet did not alter HDL-
cholesterol levels in a 1-year random, controlled study of
164 men and women (107). Dietary fat, in fact, has been
shown to increase HDL levels in mice by increasing the
transport rates and decreasing the fractional catabolic rates
of HDL-cholesterol ester and apo A-I (108).
Importance of Experimental Design in Exercise
Intervention Studies
Prospective studies to investigate whether increases in
physical activity produce beneficial changes in plasma HDL
levels in overweight individuals have also produced con-
flicting results. The response to exercise in these individuals
has been found to be heterogeneous and dependent on the
following factors: 1) the methodologic approaches used; 2)
the intensity and duration of exercise; and 3) fitness levels
achieved.
In obese men and women, exercise programs of various
intensities and durations have been reported to increase
(105,109), decrease (110), and not alter (111) HDL-choles-
terol levels. These variations in the reported effectiveness of
exercise on HDL-cholesterol have been attributed to differ-
ences in experimental design. For example, not all studies
were controlled for collateral changes in diet, smoking, and
alcohol intake, all of which can substantially alter lipopro-
tein profiles (112,113).
Second, the timing of plasma collection can have a pro-
found effect on HDL-cholesterol levels (112). Exercise ex-
erts an acute effect on plasma lipids, distinct from its
chronic effects because of training and weight loss. For
example, 40 minutes of continuous treadmill exercise in
nine healthy women led to transient increases in HDL-
cholesterol levels that returned to baseline values within 24
hours (114). Such increases in HDL with acute exercise
have been attributed to transient increases in lipoprotein
lipase activity and clearance of triglyceride-rich lipoproteins
from the circulation (115), which, as discussed above, can
alter the composition and catabolic rate of HDLs. Thus,
studies that measure the effects of exercise-induced weight
loss on HDL-cholesterol levels at steady-state conditions
before, during, and after exercise sessions would tend to be
more reliable.
Third, differences in plasma volumes across subjects
were not accounted for in all exercise intervention studies
(112). Because plasma volume expands with training,
plasma samples uncorrected for changes in an individual’s
plasma volume would tend to underestimate the effect of
exercise on plasma HDL levels (116). Weight loss, con-
versely, reduces plasma volume, and, therefore, plasma
samples may overestimate its effect on HDL levels (117).
Finally, the number and attributes of the subjects studied
can contribute to differences in exercise-mediated changes
in HDL-cholesterol. Obviously, a randomly designed study
conducted on a large sample population group would tend to
increase the accuracy and probability of detecting signifi-
cant differences in HDL levels. Furthermore, a greater im-
provement in HDL-cholesterol responses to exercise seems
to occur in men compared with women and in more severely
obese individuals. Differences in baseline HDL-cholesterol
levels among individuals may have contributed to the het-
erogeneous responses to exercise in different sample popu-
lations. Subjects with higher initial HDL-cholesterol levels
(women and individuals with less relative body weight and
BMI) may not experience the magnitude of increase in
HDL-cholesterol seen in subjects with lower baseline values
(men and individuals with greater initial body weight and
BMI) (106,113).
Mechanisms of Exercise-induced Elevations in HDL
Levels
Several studies have compared the effects of exercise and
weight loss per se (as a result of hypocaloric dieting) on
HDL-cholesterol changes in obese subjects. Wood et al.
(107) showed, in a random, 1-year controlled study of 84
overweight sedentary men, that moderate exercise mediates
a greater increase in total HDL- and HDL2-cholesterol per
kilogram body weight loss than hypocaloric dieting. Simi-
larly, Sopko et al. (118) reported that moderate exercise and
weight loss mediate separate and independent effects on
HDL-cholesterol and that their effects are additive. The
above studies, combined with the evidence that decreases in
body fat are more easily attained and maintained when
exercise is part of a weight-loss program (119), underscore
the greater effectiveness of exercise in raising HDL-choles-
terol levels than dieting.
Exercise mediates a positive effect on HDL3b, HDL2b,
and HDL apoA-I components, at least partly through
changes in enzymes of lipoprotein metabolism. In one
study, the biological half-life of HDL apoA-I was found to
be ⬃1.5-fold greater in endurance-trained men vs. sedentary
controls subjects (116). An 80% greater lipoprotein lipase
activity and 38% lower hepatic lipase activity were also
found in the endurance-trained group. Therefore, increased
lipid transfer to HDL by lipoprotein lipase and/or reduced
HDL clearance by hepatic lipase were believed to account
for the prolonged apo A-I half-life in the trained men.
In a later prospective study, Kiens and Lithell (120)
showed that endurance training directly increased lipopro-
tein lipase activity in skeletal muscle tissue. Schwartz and
Brunzell (121) found that, in obese individuals, lipoprotein
lipase activity in adipose tissue increased with weight sta-
bilization at a reduced weight (through hypocaloric dieting)
and, conversely, returned to baseline levels with weight
gain. Although it has not been specifically tested (to our
knowledge), the independent effects of exercise and weight
OBESITY Vol. 15 No. 12 December 2007 2883
Obesity and High-density Lipoproteins, Rashid and Genest
loss per se may be attributed to different tissue-specific
alterations in lipoprotein lipase activity.
Role of Exercise Intensity, Duration, and Training on
HDL-cholesterol
There is evidence to indicate that improvements in HDL-
cholesterol levels occur only when threshold exercise inten-
sities or duration are reached (122–126). Evaluation of
serum lipoproteins in overweight/obese postmenopausal
women after 1 year of moderate-intensity exercise showed
no change in HDL levels from baseline values (122). Wil-
liams et al. (124) reported that plasma HDL-cholesterol
concentrations in healthy, middle-age, sedentary men did
not change with endurance running unless they ran at least
10 mi/wk at 70% to 85% of maximum exercise intensity
over a period of 9 months. Post hoc analysis of 6849
non-smoking runners of varying BMI further revealed that
HDL-cholesterol levels increased by 0.2 mg/dL and BMI
decreased by 0.05 kg/m2 with every 1-mi increase in dis-
tance run per week (125). Further analysis revealed that the
number of miles run per week required to significantly
increase HDL, decrease the total cholesterol-to-HDL ratio,
and decrease triglycerides was much greater than the num-
ber needed to reduce BMI.
Thompson et al. (127) observed that, even with prolonged
exercise training (8 to 11 months) of high intensity (1 hour
supervised exercise training on bicycle ergometers at 80%
of maximum heart rate), changes in HDL-cholesterol con-
centration are modest (an average of 13% or 5 mg/dL).
However, because cardiovascular risk decreases by 1% to
2% for every 1- to 2-mg/dL increase in HDL (128) and
because physical activity per se is cardioprotective, weight
loss achieved through exercise likely represents substan-
tially decreased CAD risk in obese individuals.
Conclusions and Future Directions
From the preceding sections, it is clear that excess weight
and adiposity are linked to low HDL-cholesterol levels in
obese individuals. The fact that low HDL levels in obese
states can be increased with reduction of adiposity suggests
(but does not prove) a causal link. The relationship among
obesity, HDL-cholesterol levels, and CAD risk could, per-
haps, be more closely studied in humans by administering
an HDL-raising agent or placebo randomly to a select
population with low HDL-cholesterol levels and varying
degrees of obesity and examining clinical CAD endpoints.
The effects of confounding factors affecting HDL-choles-
terol levels (e.g., smoking, alcohol, diet, other dyslipi-
demias) would have to be carefully controlled.
Furthermore, the mechanisms contributing to HDL-cho-
lesterol lowering in obese subjects need to be more pre-
cisely elucidated. Animal models that more closely mimic
the human lipoprotein profile than presently available (e.g.,
2884 OBESITY Vol. 15 No. 12 December 2007
the fatty Zucker rat) should help in this regard. Also, more
studies on the effect of obesity on the molecular mecha-
nisms of HDL metabolism (receptor and post-receptor
mechanisms) need to be carried out.
Finally, a caveat to consider in non-pharmacologic ap-
proaches to weight loss and increasing plasma HDL con-
centrations is the behavioral and metabolic resistance of
overweight individuals to weight loss. Only 5% of over-
weight subjects are able to achieve and maintain weight loss
for a prolonged period of time (129). Metabolically, this
may partly be a result of an existing set point for fat mass or
fat cell size (121). Therefore, a combination of behavioral,
diet, and exercise interventions may be required to attain
and maintain weight loss and improvements in HDL-cho-
lesterol levels in obese subjects.
Acknowledgment
S.R. is supported by a Canadian Institutes of Health
Research Fellowship.
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