Critical Review

Sexual Dimorphism in Human Lipid Metabolism1

Bettina Mittendorfer2
Division of Geriatrics and Nutritional Sciences, Washington University, School of Medicine, St. Louis, MO

ABSTRACT The existing work demonstrates that striking differences exist between men and women in lipid
kinetics. These differences cannot be explained simply by the presence and action of sex hormones and are not
always due to secondary, phenotypic traits that characterize men and women (e.g., body-composition, regional fat
distribution). In fact, some of these secondary traits may even be the result of sexual dimorphism in metabolism,

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and being of female or male genotype also determines intermediary metabolism. This review provides an overview
of the currently available information regarding sexual dimorphism in human lipid metabolism but does not provide
an in-depth account of current knowledge (due to limited space); it will be a broad introduction to those interested
in the field and will, hopefully, stimulate further efforts to unravel the secrets of male and female metabolism. What
has been discovered so far regarding differences in lipid metabolism between men and women is likely only the tip
of the iceberg; clearly, more work is necessary to fully understand human substrate metabolism and the implica-
tions the presence of sexual dimorphism in the control of substrate kinetics has on the prevention and treatment
of disease. J. Nutr. 135: 681– 686, 2005.

KEY WORDS: ● fatty acid ● lipolysis ● triglyceride

Within the past decade, a great deal of effort has been
dedicated to uncovering the relevant physiologic differences
between the sexes that may affect the prevention, diagnosis,
and treatment of disease. For example, there are differences
between the sexes in the lipid profile that may have clinical
implications. In women, high plasma triglyceride (TG)3 con-
centrations are independent and better predictors of cardio-
vascular disease risk than total or LDL cholesterol (1,2). Treat-
ment of hypertriglyceridemia may, therefore, be of greater
importance in women than in men. Also, differences in he-
patic handling of fatty acids between men and women are
likely responsible for the greater susceptibility of women to
fatty liver disease and the more severe liver injury as a result of
it (3). A better understanding of the control of lipid metabo-
lism by a person’s sex will therefore not only increase our
knowledge of human intermediary and macronutrient metab-
olism, but may also be useful for the development of novel
approaches for the treatment and prevention of disease.
There are 2 general approaches when evaluating differences
in metabolism between the sexes. One (clinically probably the
most relevant) is to accept the differences in phenotype be-
tween men and women (e.g., body composition, regional fat
distribution, aerobic fitness, all of which affect substrate me-
tabolism in persons of the same sex) and acknowledge that the
1
Support was received from the U.S. National Institutes of Health grants HD
01459, AR 49869, DK 56341 (Clinical Nutrition Research Unit at Washington
University), and grants from the Novo Nordisk, the Danish Natural Sciences
Foundations, and the Danish National Research Foundation (Center for Inflam-
mation and Metabolism grant).
2
To whom correspondence should be addressed.
E-mail: mittendb@wustl.edu.
3
Abbreviations used: LPL, lipoprotein lipase; Ra, rate of appearance; TG,
triglyceride.
observed differences in lipid metabolism may be secondary to
those characteristics. The other strives to eliminate as many
potential confounding variables as practically feasible to de-
termine whether sex per se represents an underlying factor in
the control of metabolism.
A simple view concerning the underlying cause for sexual
dimorphism in metabolism would be to blame it on the pres-
ence and known action of the sex hormones. However, we are
now starting to discover that many genes are actually ex-
pressed in a sexually dimorphic manner, and there is evidence
for differences in post-translational changes in men and
women (although the mechanisms are mostly unknown); this
will almost certainly result in different enzyme activities,
abundance of cellular signal transduction elements, and con-
sequently, in substrate kinetics. Furthermore, the association
of many gene polymorphisms [e.g., (4 – 6)], associated with risk
factors for disease and substrate kinetics is also often sex
specific (Fig. 1).
The aim of this article is to review the major findings on
differences of human fatty acid and TG metabolism between
men and women in the basal, overnight fasted state and during
the major physiologic challenges that affect lipid metabolism,
i.e., food intake and hyperinsulinemia/hyperglycemia, exer-
cise, and short-term fasting. Reference to women in the fol-
lowing sections refers to premenopausal women unless specif-
ically indicated otherwise.
Fatty acid kinetics
Circulating fatty acids, derived from the breakdown of
endogenous TG that are stored in adipose tissue and muscle,
are an important source of fuel. Insulin is the major regulator
of basal and postprandial lipolytic rates (7), whereas cat-

0022-3166/05 $8.00 © 2005 American Society for Nutritional Sciences.

Manuscript received 14 December 2004. Initial review completed 27 December 2004. Revision accepted 12 January 2005.

681
682 MITTENDORFER
FIGURE 1 Factors involved in sexual dimorphism of intermediary
metabolism.
echolamines are important for stimulating lipolysis during
metabolic stress. The release of fatty acids into the blood-
stream is stimulated during conditions of “glucose-shortage”
(e.g., fasting, exercise) to meet the increased demand and
inhibited when glucose is available to cover fuel requirements
(Fig. 2). An imbalance between the release and utilization of
fatty acids leads to elevated plasma fatty acid concentrations,
which is associated with increased plasma TG concentrations
and insulin resistance and, most likely as a result of that, an
increased risk for the development of cardiovascular disease
(8). The following sections will provide an overview of our
current knowledge concerning differences between men and
women in fatty acid kinetics during basal, postabsorptive con-
ditions, and the major physiologic conditions that inhibit
(meal intake/hyperinsulinemia) and stimulate (exercise and
fasting) lipolysis. The amount of information available for
each of these topics varies greatly, with exercise clearly being
the most extensively studied field.
Basal, postabsorptive state
Early studies that used isotope tracer methods found that
the basal rate of appearance (Ra) of fatty acids in the blood-
stream is greater in women than in men (9,10). The women in
those studies had more body fat, relative to lean mass; thus, it
was not clear how much of the greater lipolytic rate was
attributable to the excess fat mass, which can independently
cause a higher lipolytic rate (11,12). We measured glycerol Ra
in plasma (an index of whole-body lipolytic rate) in men and
women who were matched for percentage of body fat to
eliminate the potential influence of differences in adiposity,
and we studied the women in the early follicular phase to
minimize the variability and potential influence of female sex
hormones on lipolysis. We also found higher rates in women
than men, probably because of higher circulating insulin con-
centrations, and therefore greater suppression of lipolysis in
the men than in the women. However, the difference in
plasma insulin concentration was likely not the sole factor
contributing to the differences in lipolysis. First, men appear to
be less sensitive to the antilipolytic effects of insulin (see
below); second, Nielsen et al. (13) discovered that fatty acid
Ra is highly correlated with resting energy expenditure, but
that women have a different set-point and higher rates of fatty
acid release in relation to their energy requirements. Release of
“excess” fatty acids in women may be advantageous during
times of increased fuel requirements but may also challenge
tissues such as the liver, which could explain the greater
susceptibility of women to develop fatty liver disease than men
(3), once the capacity for hepatic VLDL-TG secretion is
reached.
Food intake/hyperinsulinemia
Insulin stimulates glucose uptake by tissues in response to
food intake and is the major regulator of lipolysis (14 –16). No
study has compared the inhibitory effect of insulin on adipose
tissue lipolytic activity in men and women, but it appears that
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women are more sensitive to its effects. The suppression of
plasma fatty acid concentrations during an oral glucose toler-
ance test (17) and suppression of oleate Ra (18) after a
standard meal were greater in women than in men, predomi-
nantly because of the resistance of men’s upper-body subcuta-
neous adipose tissue to insulin (18). These findings are partic-
ularly striking because women in those studies were fatter than
men and increased body fat mass is associated with a reduced
sensitivity of adipose tissue to the effects of insulin (19). The
greater sensitivity of women to the antilipolytic effect of
insulin probably compensates, at least in part, for the higher
basal fatty acid flux and helps maintain overall fatty acid
homeostasis. In addition to the differences between men and
women in the response of the endogenous release of fatty acids
during hyperinsulinemia/meal intake, there are also differences
in the handling of meal TG-bound fatty acids. Compared with
women, men take up a considerably greater proportion of
exogenous fatty acids in splanchnic tissues (20), whereas
women store a greater percentage (⬃40 vs. 25%) of dietary
fatty acids in subcutaneous adipose tissue (21). This phenom-
enon likely contributes to the greater fat storage in visceral
adipose tissue in men (22). The reasons for the sex-dependent
regional channeling of dietary fatty acids are unknown; we
can, however, rule out testosterone as one of the possible
causes because administration of testosterone, which caused a
FIGURE 2 Relation between fatty acid and triglyceride metabo-
lism in the major organs involved in lipid metabolism.
 SEXUAL DIMORPHISM IN HUMAN LIPID METABOLISM
doubling of its concentration in plasma, reduced the storage of
dietary fatty acids in visceral and retroperitoneal adipose tissue
and increased the storage in subcutaneous adipose tissue (23).
The effects of female sex hormones (or lack thereof) on
regional fatty acid storage have not been studied to date.
Exercise
Evaluating lipid kinetics in men and women during exercise
is particularly difficult because it is affected by body composi-
tion, aerobic fitness, and training status, age, menstrual cycle
phase (during high-intensity exercise), and possible other less
explored factors such as muscle fiber-type composition (24,25).
This may explain in part the often controversial results in the
literature. For example, several studies found that the rate of
fat oxidation was higher in both untrained and trained women
than men, whereas others found that women use more fat and
less carbohydrate than men; still others were unable to report
differences between the sexes (25). To avoid those confound-
ing influences, we recently examined lipid metabolism during
moderate-intensity endurance exercise in young adult men
and women who were matched for fatness, aerobic fitness, and
age (26). We found that fatty acid Ra [and rate of disappear-
ance (Rd)] during exercise was greater in women than in men,
but that the rate of total fatty acid oxidation did not differ
between the 2 groups. Compared with men, however, women
oxidized more plasma free fatty acids, derived primarily from
adipose tissue TG, and less nonplasma fatty acids, presumably
derived primarily from intramuscular TG and possibly VLDL-
TG. The greater reliance on plasma free fatty acids as a fuel in
women than men was likely a result of greater availability of
those fatty acids in women than in men. Contradicting those
findings, studies performed at the August Krogh Institute in
Copenhagen (27,28) suggested that intramuscular TG use
during exercise, determined by evaluating fat content in mus-
cle biopsies, is actually greater in women than men, who were
matched for aerobic fitness but not body composition. Limi-
tations in using intramuscular TG content as a measure of
intramuscular TG oxidation during exercise and differences in
matching men and women on body composition may be re-
sponsible for the discrepancy between studies. The mecha-
nism(s) responsible for the differences between the sexes in
lipolysis of adipose tissue TG observed in our subjects during
exercise is not entirely understood but is partly related to
differences in lipolytic sensitivity to ␤-adrenergic stimulation
and ␣-adrenergic receptor activity [see (24,25)]. Most of the
increase in lipolytic activity that occurs during exercise is
mediated through catecholamine stimulation of adipose tissue
␤-adrenergic receptors; although ␣-adrenergic receptor activ-
ity was also shown to inhibit lipolysis during exercise, thereby
counteracting the ␤-adrenergic effect in men, it is not in-
volved in the regulation of lipolysis during exercise in women.
Excess body fat blunts the relative increase in fatty acid Ra
induced by endurance exercise in both men and women (29 –
31). However, the mechanism responsible for the blunted
lipolytic response to exercise associated with obesity may differ
in men and women. First, we (30) and others (32,33) found
that exercise causes a smaller increase in plasma epinephrine
concentration in obese than in lean men, whereas the cate-
cholamine response during exercise does not differ in lean and
obese women (29,31,34). Furthermore, unlike obese men (35–
37), adipose tissue ␤-adrenergic receptor sensitivity is de-
creased in obese women (30), whereas ␣-adrenergic receptor
stimulation during exercise is greater in both obese men and
women compared with lean subjects (38). Therefore, the com-
posite of these data suggests that there is sexual dimorphism in
683
the adrenal medullary response to exercise and in adipose
tissue lipolytic response to epinephrine stimulation in obese
subjects.
Information regarding the metabolic response to exercise
training in men and women is controversial. In one study,
exercise training caused a greater increase in fat oxidation
during exercise in women than in men (39 – 41). However,
these findings were confounded by the fact that the increase in
aerobic fitness was also greater in women (25%) than in men
(9%). In another study, 12 wk of endurance training in women
increased total fat oxidation by ⬃25% during exercise per-
formed at the same absolute intensity (15). This response is
the same as that reported in men after a similar training-
induced increase in fitness (42,43). When plasma free fatty
acid oxidation was assessed by isotope tracer methods, and
whole-body fat oxidation was assessed simultaneously by indi-
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rect calorimetry, it was found that the training-induced in-
crease in fat oxidation was due primarily to an increase in the
oxidation of nonplasma fatty acids, presumably intramuscular
TG (15). In contrast, Steffensen et al. (28) found no effect of
training status on intramuscular TG use between men and
women, when TG content was measured in muscle biopsies
during moderate intensity exercise, and exercise was per-
formed at the same relative intensity in a cross-sectional study
of untrained, moderately, and highly trained subjects. How-
ever, total fat oxidation was higher in highly trained than
sedentary and moderately trained subjects. The reason for the
discrepancy in the source of oxidized TG between studies is
not clear but may be related to differences in study design
(longitudinal vs. cross-sectional analysis) and the methods
used to assess intramuscular TG use (muscle biopsy vs. isotope
tracer and indirect calorimetry techniques).
Fasting
The initial response to fasting is characterized by an in-
crease in the mobilization of adipose tissue TG and a decrease
in the production and oxidation of glucose. Studies that were
performed many years ago showed that the increase in plasma
fatty acid and ketone body concentrations (44 – 46) is greater
in women than in men. These findings may at first suggest that
the mobilization of fatty acids from adipose tissue is likely
greater in women than in men during fasting. However,
plasma substrate concentration represents the balance be-
tween substrate delivery into plasma and substrate tissue up-
take but does not provide information regarding the dynamic
metabolic events responsible for the observed concentrations.
In fact, contrary to these earlier studies, we found that the
relative increase in glycerol Ra during brief fasting was greater
in men than in women, most likely because of both higher
basal plasma insulin concentrations and a greater increase in
epinephrine release during fasting in men (47). The relatively
blunted lipolytic response in women may be beneficial by
preventing excessive and potentially harmful increases in
plasma fatty acid concentrations (48).
Sex hormones
Little information is available regarding the direct effect of
sex hormones on human fatty acid metabolism. That is un-
doubtedly due to the undesirable side effects when adminis-
tering sex hormones in excess or to the opposite sex, or
blocking their action. Surprisingly, the literature does not
satisfactorily cover those gaps with data from studies in ani-
mals, and studies of postmenopausal women or hypogonadal
men. There is evidence that variations in circulating female
684 MITTENDORFER
sex hormones can affect substrate kinetics during extreme
physiologic conditions such as high-intensity exercise (49);
however, fatty acid kinetics were the same during the follicular
and luteal phases of the menstrual cycle during basal and many
other conditions (49 –53). Interestingly, administration of es-
trogen to postmenopausal women increased basal fatty acid Ra
(54); however, this was only a ⬃10 –20% increase, probably
too small a difference to be detected during normal fluctua-
tions of the menstrual cycle. It is also possible that progester-
one may counteract the effects of estrogen, but the effects of
progesterone on the control of human lipid metabolism have
not been systematically studied. Also, at odds with the findings
that basal lipolytic rates are higher in women than men (see
above), are the results from studies in which testosterone
administered to obese men for 2 mo increased abdominal
adipose tissue turnover (23). In adipocytes cultured in vitro
(55,56), testosterone had no effect on the basal rate of lipolysis
but increased the responsiveness of the adipocytes to isopro-
terenol and forskolin. The physiologic relevance of those
findings is unknown because adipose tissue lipolytic sensitivity
is similar in men and women when adipocytes are isolated and
exposed to physiologic concentrations of catecholamines (57–
60) and in vivo during catecholamine infusion (10,61).
Plasma triglyceride kinetics
Chylomicrons and VLDL contain the greatest amount of
TG in the fed and fasted states, respectively. Triglycerides in
chylomicrons and VLDL are progressively hydrolyzed by li-
poprotein lipase (LPL) present in muscle and adipose tissue
capillary endothelia (62), and the resulting fatty acids are
taken up by local tissues, where they can be oxidized for fuel or
stored as TG. Alterations in lipoprotein metabolism are in-
volved in the pathogenesis of cardiovascular disease. Epidemi-
ologic studies demonstrated a direct relation between both
fasting and postprandial plasma TG concentration and the risk
for the development of cardiovascular disease, especially in
women (1,2,63,64). Moreover, an increase in fasting plasma
TG concentration is often associated with a decrease in plasma
HDL cholesterol (1), which also contributes to the risk for
cardiovascular disease (65) and that more so in men than in
women (2). Despite increasing evidence that alterations of the
plasma lipid profile that pose a risk for the development of
disease and vice versa are associated with certain diseases differ
greatly between men and women, few studies have been de-
signed to better understand lipoprotein metabolism in the 2
sexes.
Basal, postabsorptive VLDL-TG kinetics
We demonstrated recently that sex, independent of body
fatness, has a substantial effect on basal VLDL-TG kinetics
and the relation between VLDL-TG kinetics and plasma TG
concentration. We found that VLDL-TG secretion rates were
greater in lean women than in lean men, and the rate of
VLDL-TG secretion rate increases with increasing amounts of
body fat in men but not in women (66). This is probably due
to the greater availability of nonsystemic fatty acids for VLDL-
TG production in obese men, likely because of greater visceral
fat accumulation in obese men compared with obese women
(22). Furthermore, the concentration of plasma VLDL-TG
concentration was directly related to basal VLDL-TG produc-
tion in men, but was inversely related to VLDL-TG clearance
in women. There is some evidence that adipose tissue and
skeletal muscle LPL activity may be affected by both sex and
obesity (35–39); the results from different studies, however,
are inconsistent. Sex differences appear to also exist in the rate
of secretion of VLDL-apolipoprotein B; in this case, however,
the secretion rate is higher in men than women (67), which
suggests that the VLDL particles secreted in men are smaller
than those in women, consistent with data that measured
concentrations of different size VLDL particles in the blood-
stream (68). Differences in the particle size may contribute to
the differences in risk for the development of cardiovascular
disease (69) between men and women.
VLDL-TG kinetics during hyperglycemia-hyperinsulinemia/
meal intake
Decreasing endogenous VLDL-TG production during post-
prandial conditions is important for regulating whole-body TG
flux when dietary TG are entering the systemic circulation via
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chylomicrons. A suppression of VLDL-TG production during
feeding is probably mediated in large part by the glucose-
induced stimulation of insulin secretion; a euglycemic-hyper-
insulinemic clamp lowered the rate of secretion of VLDL-TG
into plasma, in lean and obese women (no data are available
in men) with no difference in the magnitude of the effect
between the lean and obese. However, this conclusion may
not be robust because VLDL-TG production rate was deter-
mined by using a tracer method that did not account for
hepatic tracer recycling, which can have considerable effects
on the calculation of VLDL-TG kinetics (70). We examined
the effect of hyperglycemia-hyperinsulinemia induced by glu-
cose infusion (to achieve postprandial plasma glucose and
insulin concentrations) on VLDL-TG metabolism in lean and
obese men and women. Glucose infusion markedly decreased
VLDL-TG production in lean and obese men and lean
women, but not in obese women. The blunted response in
obese women occurred despite plasma fatty acid concentra-
tions similar to those in the other groups. These data demon-
strate that sex and adiposity affect the glucose/insulin-medi-
ated suppression of VLDL-TG production and suggest that
plasma fatty acid availability, despite the common belief that
it is the main regulator of VLDL-TG production, may not be
the primary regulator of VLDL-TG metabolism, at least in
obese women. Data from several studies that suggest that
VLDL-TG production is controlled largely by hepatic fatty
acid availability were obtained under conditions that do not
always mimic physiologic conditions (e.g., fatty acid concen-
trations were raised several fold above the normal range ob-
served throughout a day) or were confounded by the methods
used (e.g., heparin, which stimulates lipoprotein lipase activity
and likely TG turnover, was given to raise fatty acids). In
addition, the availability of fatty acids for VLDL-TG produc-
tion depends also on fatty acid delivery to the liver from
peripheral and intrahepatic and intraperitoneal adipose tissue
TG and fatty acids that are newly synthesized. Furthermore,
insulin may also inhibit VLDL-TG production by a mecha-
nism that is independent of its effect on fatty acid availability.
In fact, it was found that insulin infusion suppressed VLDL-
TG production even when the insulin-mediated decrease in
fatty acid availability was prevented (71). The mechanism(s)
responsible for the impaired suppression of VLDL-TG produc-
tion during glucose infusion observed in the obese women in
our study is not known but our findings are consistent with
studies that investigated the effect of insulin on plasma VLDL-
TG concentration. Lewis et al. (72) found that plasma VLDL-
TG concentration decreased in response to hyperinsulinema
in lean but not in obese women (72), and Bioletto et al. (73),
who compared a group of obese men and women with lean
men only found that the insulin-induced decrease in plasma
 SEXUAL DIMORPHISM IN HUMAN LIPID METABOLISM
VLDL-TG concentration was blunted in the obese compared
with the lean.
Postprandial lipemia
The postprandial lipemic response, which is characterized
by the change in total TG and TG-rich lipoprotein concen-
trations in plasma in response to dietary fat intake, is deter-
mined predominately by the fat content of a meal. However,
other factors, such as meal fatty acid composition, body-com-
position (i.e., total body fat, visceral fat accumulation), insu-
lin-sensitivity, and physical activity, also play a role in the
postprandial lipemic response (74 –77). Postprandial plasma
TG concentrations are lower in women than men (77). The
differences can be attributed largely to differences in body-fat
distribution (and differences in insulin sensitivity associated
with it) because the differences between the sexes disappeared
when men and women were matched for visceral adipose tissue
accumulation (77), whereas women who had the same amount
of total body fat (but likely less visceral adipose tissue than
men) also had a smaller response than men (76).
Exercise
The plasma TG lowering effect of exercise was recognized
several decades ago [e.g., (78)]. However, the exact mecha-
nisms responsible for the hypotriglyceridemic effect of exer-
cise, which appears to result predominantly from a decrease in
VLDL-TG, both during fasting and fed conditions, are still
unknown. Furthermore, most of the studies that investigated
the effect of exercise on plasma TG concentrations were
performed in lean, frequently trained men, but not in obese
persons and women.
In conclusion, having established that women differ from
men metabolically, focus should be directed to better under-
stand metabolism in women, not only to complement the
knowledge we have obtained in men over many years, but also
because of its clinical implications in terms of understanding
the metabolic consequences of maintenance of good health
and the treatment of disease.
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