Role of Gonadal Steroids in the Sexual Dimorphisms in Body Composition and Circulating Concentrations of Leptin1
Michael Rosenbaum and
Rudolph L. Leibel
Department of Pediatrics, Division of Molecular Genetics, New York
Presbyterian Hospital, New York, New York 10032
Address all correspondence and requests for reprints to: Michael Rosenbaum, M.D., Russ Berrie Research Building, 1150 St. Nicholas Avenue, 6th Floor, New York, New York 10032. E-mail:
mr475{at}columbia.edu
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Introduction
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THE NUMBER of calories stored as fat
(adipose tissue) influences systems of energy homeostasis (energy
intake and expenditure) and endocrine function (somatic growth,
fertility, lactation, glucose homeostasis, and thyroid function) (1).
This relationship, sometimes referred to as the lipostatic model (2),
requires that a signal from (or otherwise proportionate to the mass of)
adipose tissue is sensed by central nervous system neurons, whose
efferents affect energy homeostasis (appetite and/or energy
expenditure) and endocrine function. The ob gene product,
the protein leptin, is secreted from adipose tissue in direct
proportion to fat mass and is capable of providing such a signal
(3).
Regardless of how body composition is measured, at the same body
weight, women generally have a larger adipose tissue mass (4, 5) and
have higher circulating concentrations of leptin per unit of fat mass
than men (6, 7, 8). These sexual dimorphisms are predominantly accounted
for by gonadal steroids (see below) and indicate that systems
regulating energy homeostasis (energy intake and expenditure and the
partitioning of stored calories between fat and lean body mass) are
also strongly affected by the gonadal hormones.
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Body composition
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Absolute measures of body fat or water content (fat mass and
fat-free mass) must be distinguished from measures of fractional body
fat (body fatness) calculated as the ratio of fat mass to total body
weight or from various permutations of the relationship between weight
and height [e.g. body mass index (BMI) = weight
(kilograms)/height (meters)2] (9). Body composition
analysis describes the mass of specific chemical components that, when
totaled, equal the body weight of the individual. Depending upon the
methodology employed, a two-compartment (fat mass and fat-free mass) or
multicompartment (fat, water, calcium) model may be generated. In
addition, newer scanning techniques, such as nuclear magnetic resonance
spectroscopy or dual energy x-ray absorptiometry, permit analysis of
the anatomical disposition of these constituents of body composition.
Thus, sc fat can be distinguished from visceral fat, and the masses of
brain, muscle, liver, bone, etc. can be estimated (10, 11).
A two-compartment model is adequate to describe total energy stores and
can be generated by densitometry, isotope dilution, measurement of
skinfold thicknesses, body electrical conductivity, or bioimpedance
(12, 13, 14). It should be emphasized that none of the above methods
provides a direct measure of body composition. Dual energy x-ray
absorptiometry (15) provides a more direct measure of body composition
as well as information regarding body fat distribution and bone mineral
density (1, 16, 17), which, as discussed below, are important measures
for assessment of the risk of adiposity-related morbidity and
osteoporosis. Precise means of directly measuring body composition are
not readily available to the clinical practitioner. Current
recommendations are to consider an individual to be at risk for
adiposity-related morbidity if his/her BMI is greater than 25
kg/m2 (overweight) and to be obese if his/her BMI is
greater than 30 kg/m2 (9). These definitions are meant to
alert the practitioner regarding levels of body fatness that may convey
increased risk of adiposity-related morbidities rather than to provide
rigid diagnostic guidelines.
Genetic predispositions, as reflected by a family history of diabetes,
hyperlipidemia, or cardiovascular disease, as well as the relative
centrality of body fat distribution (see below), as reflected by a high
waist to hip ratio (>0.90 in females, >1.00 in males), also
constitute significant risk factors for these moribidities at any given
body weight (1). The risk of adiposity-related morbidities
(e.g. diabetes, hypertension, or dyslipidemia) is better
correlated with visceral adipose tissue mass than with relative body
fatness (18, 19, 20, 21). The mechanism for the association between body fat
distribution and morbidity is believed to be related to the direct
venous drainage of the intraabdominal fat depot into the portal
circulation. The high concentrations of free fatty acids thus presented
to the liver favor increased synthesis of low density and very low
density lipoproteins and promote insulin resistance by interfering with
first pass catabolism of insulin by the liver (22, 23). The overall
lower rate of cardiovascular morbidity in premenopausal females,
despite their greater body fatness (see below), is probably related in
part to the proportionally greater amount of fat in sc vs.
visceral depots in women vs. men. Visceral adipose tissue
constitutes approximately 5% of the total fat mass in premenopausal
women vs. 10% in men (24).
Adipose tissue possesses estrogen, androgen, and progesterone receptors
(25, 26), and expression of these receptors varies by depot (visceral
vs. sc) and gender (27, 28). Androgen receptors are more
dense in visceral than sc adipose tissue in both sexes, whereas the
estrogen-binding capacity of visceral adipose tissue depots is lower
than that of sc adipose tissue in males, but not females (27, 28).
Ovine studies have shown higher concentrations of the progesterone
receptor in sc (gluteal) than visceral (perirenal or omental) adipose
tissue depots (29).
Gonadal steroids largely account for the greater degree of body fatness
in women. Genetic males with testicular feminization (insensitivity to
androgens) have a female body habitus (30). Women given exogenous
androgens or suffering from virilizing tumors or disorders such as
congenital adrenal hyperplasia will develop a male body habitus,
including more central adipose tissue distribution (27, 31, 32, 33).
Cessation of gonadal estrogen production at menopause is associated
with an increase in the waist to hip ratio and size of the visceral
adipose tissue depot (24, 27, 34, 35), i.e. development of a
more android body habitus. Administration of estrogen to postmenopausal
women is associated with a lowering of the waist to hip ratio (36).
Progesterone administration to rodents increases fat mass (37), but the
addition of progesterone to estrogen as a hormone supplement for
postmenopausal women does not alter the effects of estrogen
administration on body fat distribution (36). In addition, estrogen
administration increases the concentration of progesterone receptors in
adipose tissue (29). Thus, estrogens and progesterone may act
synergistically to favor the storage of excess calories as fat, whereas
estrogens promote the storage of fat in more peripheral adipose tissue
depots. The virilization of the body composition of women with
androgen-producing tumors, even in the presence of normal female
circulating concentrations of estrogen, indicates that androgens favor
an increase in lean body mass and a loss of fat mass that can, under
certain circumstances, mask the effects of estrogen that promote fat
storage.
A propensity to store excess calories as fat would represent a clear
survival advantage for both sexes via the ability to survive the
prolonged periods of low caloric intake that probably plagued our
forebears. Storage of extra calories as fat would confer further
advantages to females in the form of increased fertility, increased
resources for breastfeeding offspring, and earlier menarche (1, 38, 39, 40). Genes that increase this propensity to store calories as fat
in the presence of estrogen would distinctly increase the likelihood of
conception and survival of offspring. Estrogen and androgen receptors
are expressed in neurons of ventromedial and lateral hypothalamic
nuclei that affect systems of energy homeostasis (including the arcuate
and paraventricular nuclei, which are major sites of synthesis and
transport of the orexigenic neuropeptide Y and which affect autonomic
nervous system tone and other systems that regulate energy homeostasis)
(1, 41, 42, 43, 44, 45, 46).
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Sexual dimorphism in circulating concentrations of leptin
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Initial reports of circulating leptin concentrations in humans
suggested that, for a given level of body fatness (BMI), leptin
concentrations were significantly greater in women than in men (47).
The 2- to 3-fold greater circulating concentrations of leptin in women,
even normalized to BMI, were attributed to a higher percentage of body
fat in females at a given weight or BMI (47). However, subsequent
studies have demonstrated that this sexual dimorphism persists even
when corrected for absolute measures of fat mass (which correlates with
circulating leptin concentrations with R values >0.90 within sexes)
(6, 7), fat-free mass (reflecting the potential volume of distribution
of leptin), and circulating insulin concentrations (which increase
leptin production) (3, 6, 7). In this sense, the interpretation of data
regarding circulating leptin concentrations poses a unique problem in
endocrinology because the anticipated amount of hormone is dependent
upon the mass of its secretory organ. This problem is further
compounded by the nonzero intercept of the regression line regulating
circulating leptin concentrations to fat mass. For example, we found
that the regression equation relating leptin to fat mass in lean and
obese males was leptin concentration = 0.98(fat mass (kg)) - 9.3
(r = 0.99; P < 0.0001) (6). An obese man with a
fat mass of 100 kg would, on this regression line, have a leptin
concentration of 89.7 ng/mL and a predicted leptin to fat mass ratio of
0.897 ng/mL·kg. A lean man with a fat mass of 20 kg would have a
leptin concentration of 10.3 ng/mL and a predicted leptin to fat mass
ratio of 0.515 ng/mL·kg. If leptin concentrations per U fat mass were
the only parameter examined, it might be erroneously concluded that
many obese individuals maintain abnormally high concentrations of
leptin per U fat mass (are leptin resistant or overproducing leptin).
However, obese and lean subjects, in general, plot on the same
regression line relating blood leptin concentrations to fat mass.
Having said this, it should also be noted that there can be
considerable interindividual variation in circulating leptin
concentrations at any specific fat mass and that the relationship
between leptin and fat mass becomes nonlinear at extremely low fat mass
(48).
The pulse amplitude of leptin release from adipose tissue into blood is
2- to 3-fold higher in females than in males, but there is no apparent
sexual dimorphism in pulse frequency (49). Rates of leptin messenger
ribonucleic acid (mRNA) expression in sc adipose tissue are
significantly (
2-fold) higher in females than males (50) and in sc
than visceral adipose tissue in both sexes (51, 52, 53). This sexual
dimorphism in the relationship between circulating leptin concentration
and body fat content could be due to primary effects of gonadal
steroids, genes on the X or Y chromosomes, or the greater proportion of
sc vs. visceral adipose tissue and higher percentage of body
fat in females than in males (4, 5, 53).
Adult females have a significantly greater mass of sc adipose tissue
relative to visceral adipose tissue than males (35, 54, and Rosenbaum
M, A Pietrobelli, J Vasselli, S Heymsfield, R Leibel; submitted
manuscript). Nagy et al. (52) reported that prepubertal
girls had a significantly higher percentage of body fat and a
significantly lower fat-free mass than prepubertal boys, but noted no
significant gender-related differences in total fat mass or in the
distribution of fat in abdominal sc vs. visceral adipose
tissue (measured by computed tomography scan). Circulating
concentrations of leptin corrected for fat mass were also significantly
(
50%) greater in girls. Gender was no longer a significant
determinant of circulating leptin concentrations when corrected for
gender-related differences in body composition and adipose tissue
distribution in visceral vs. sc depots. These investigators
suggested that the sexual dimorphism in the circulating
concentration of leptin in children was due to sex-related differences
in sc vs. visceral adipose tissue volumes, even though no
statistically significant sexual dimorphism in adipose tissue
distribution was found. However, the relatively small amount of
visceral (510% of total adipose tissue mass), relative to sc adipose
tissue in most humans of either sex (35, 54) makes it unlikely that
differential rates of leptin production in adipose tissue from these
depots (50, 53) would be sufficient to account for the striking sexual
dimorphism in circulating concentrations of leptin. Furthermore, even
within specific adipose tissue depots, leptin mRNA expression rates are
approximately 2-fold higher in women than in men (56). Therefore, a
strictly anatomical basis for the sexual dimorphism in circulating
concentrations of leptin is unlikely.
Leptin concentrations in cord blood are significantly lower in male
compared to female neonates (57), and circulating concentrations of
leptin, normalized to fat mass, are significantly greater in females
than in males at Tanner stages I, III, IV, and V in one study (58). The
observation of a sexual dimorphism in circulating concentrations of
leptin at birth and in prepubertal children in this study (52, 58)
suggests that this dimorphism is sex chromosome related. However,
numerous other studies have not detected significant gender effects on
circulating concentrations of leptin normalized to fat mass (59) or
body mass index (60) before late puberty (Tanner stage IV or V),
suggesting that the reports that leptin concentration per kg fat mass
is significantly greater in prepubertal females than males may
represent a type I statistical error due to the nonzero intercept of
the regression line relating leptin to fat mass (6, 7) discussed above.
In the two articles reporting significantly greater concentrations of
leptin corrected for fat mass in prepubertal girls (52, 58), the
average prepubertal girl had 3366% greater absolute fat mass than
the average prepubertal boy [6.5 kg in girls and 4.7 kg in boys (58);
8.3 kg in girls and 5.0 kg in boys (52)]. In the study not reporting a
significant sexual dimorphism in circulating concentrations normalized
to fat mass before puberty (60), the absolute fat mass was similar
between genders (5.1 kg in girls and 5.5 kg in boys), suggesting that
the reported value (52, 58) may be an artifact of a bimodal
distribution of body fat in the subject population.
Considering the lack of a consistent demonstration of sexual dimorphism
in leptin concentrations relative to fat mass before exposure to
endogenous gonadal steroids at puberty, the dimorphism observed in
neonates (57) is probably due to the peripubertal levels of circulating
androgens in the male fetus (61) and/or the elevated estrogens in the
female fetus (62). (Although the authors (57) noted no significant
gender differences in testosterone and estradiol concentrations in cord
blood, sexual dimorphisms in gonadal steroids are, in fact, present
from the time of Leydig cell proliferation until the perinatal
gonadotropin surge.) A primary sex chromosome-linked basis (distinct
from effects on gonad differentiation) for the sexual dimorphism in the
relationship of leptin to fat mass is, therefore, as yet unproven.
In vivo and in vitro studies support a primary
endocrine basis for this sexual dimorphism. The sexual dimorphism in
the relationship of fat mass to leptin in later puberty is eliminated
when adjusted for circulating concentrations of gonadal steroids (63).
Plasma leptin concentrations rise during early male puberty, but fall
later in puberty, suggesting that androgens may inhibit leptin
production (64, 65). Leptin concentrations are strongly negatively
correlated with circulating concentrations of testosterone in men.
Circulating plasma leptin concentrations, normalized to body mass
index, are significantly increased in hypogonadal compared to eugonadal
men, and leptin concentrations are lowered in hypogonadal men after the
administration of testosterone (66). Incubation of adipose tissue with
testosterone decreases leptin mRNA expression, and the circulating
testosterone concentration accounts for a significant fraction of the
variability in circulating concentrations of leptin in obese boys at
all stages of puberty (r = -0.35; P < 0.0001)
(67) and in adult men (r = -0.32; P < 0.01)
(68).
In contrast to males, leptin concentrations continue to rise throughout
puberty in females (65). In vivo administration of estrogen
increases circulating concentrations of leptin in humans and rodents
(8), and some studies have found that circulating concentrations of
leptin, normalized to fat mass, are slightly decreased in
postmenopausal (hypoestrogenemic) compared to premenopausal women (6, 8). Ovariectomy in adult rats causes a significant decline in
circulating leptin concentrations that is reversed by estradiol
supplementation (8). Estradiol increases in vitro leptin
production in omental adipose tissue from women, but not men (69), and
circulating concentrations of estradiol and testosterone have been
reported to be significantly correlated with plasma leptin
concentrations in adult women (70, 71), but not in female children or
adolescents (72).
Administration of estradiol and cyproterone acetate (an androgen
receptor antagonist) to transsexual males increased the circulating
plasma leptin concentration (160180%), whereas administration of
testosterone to transsexual females increased body weight and decreased
the circulating leptin concentration (-5060%) (73). In these
studies, hormonal sex, but not genetic sex, was a significant covariate
of the plasma concentration of leptin normalized to fat mass. This
conclusion is not supported by the observation that this sexual
dimorphism is not substantially altered in the hyperandrogenemic
polcystic ovarian syndrome (74, 75, 76, 77).
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Leptin, body composition, and energy homeostasis
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The hyperphagia, hypometabolism, decreased thermogenesis, and
hypothyroidism of the leptin-deficient or leptin-resistant rodent
recapitulate the metabolic adaptations of humans to hypocaloric intake
(1, 78, 79). Circulating leptin concentrations, normalized to fat mass,
are significantly negatively correlated with voluntary food intake in
postmenopausal women (80). This is exactly what is predicted by
leptin-deficient rodents and makes the case for leptin as an appetite
signal. Higher leptin leads to less desire to eat, and, by implication,
lower leptin levels (as in the rodents) leads to hyerphagia.
The relationship of circulating leptin concentration to energy
expenditure in weight-stable humans is unclear. In some studies,
significant positive correlations of plasma leptin concentrations with
resting energy expenditure or 24-h energy expenditure are found
(81, 82, 83), whereas in others no correlations (7, 84) or even significant
negative correlations between leptin and energy expenditure are noted
(85). Some of the discrepancies among these studies appear to result
from the extreme colinearity of leptin and fat mass (r2 >
0.90 in males and females) (6). Using stepwise multiple linear
regression analyses, we have examined the relationship between leptin
and energy expenditure in lean and obese subjects studied while weight
stable at their usual body weights, 10% above their usual body
weights, and 10% below their usual body weights (7). We found, as have
others (84), that there were no significant correlations between
circulating leptin concentration and 24-h energy expenditure or resting
energy expenditure at any weight plateau in lean or obese subjects. The
maintenance of an elevated body weight did not alter the relationship
between leptin and fat mass in any subject, whereas the maintenance of
a reduced body weight was associated with a significant reduction in
concentrations of leptin normalized to fat mass in women, but not in
men (7).
These findings are in contrast to the changes in energy expenditure
that accompany maintenance of an elevated or reduced body weight (86).
The process of weight loss, but not weight gain, causes a significant
decline in circulating leptin concentrations normalized to fat mass (7, 87). These observations are consistent with a threshold model for the
effects of leptin on energy homeostasis. When the circulating (hence,
central nervous system) leptin concentration falls below an
individualized threshold concentration, the hypometabolism and hunger
that characterize the weight-reduced individual or the rodent with
mutant leptin or leptin receptor genes are invoked (1). In such a
threshold model, the organism defends a minimum body fat. The storage
of moderately excessive body fat stores does not necessarily invoke any
counterregulation. In this sense, the system does not behave as if
there were an absolute set-point for body fat above or below which
there is a compensatory response. As maintenance of an elevated body
weight results in hypophagia and hypermetabolism, an alternative system
must regulate upper limits of body fatness. Operationally, such a
threshold resolves genetic, developmental, and environmental influences
and would not necessarily remain constant throughout a lifetime. The
thresholds for the wide variety of leptin-mediated physiological
effects (3) are probably different. For example, effects on the gonadal
or adrenal axis can be achieved without effects on food intake
(79).
If such a threshold model is correct, there should be demonstrable
effects of gonadal steroids on systems regulating energy homeostasis,
even though men and women demonstrate similar metabolic rates
normalized to fat-free mass and make similar adaptations to under- and
overfeeding (86). If leptin sensitivity or threshold were not
influenced by gonadal steroids, then the hypogonadal males or
transsexual females who received testosterone (66, 73) should display
similar hyperphagia and hypometabolism as a result of the decline in
circulating concentrations of leptin accompanying such treatment. They
should, in this instance, attempt to rectify their lower circulating
concentrations of leptin by increasing adipose tissue mass. This is
clearly not the case, as hyperandrogenized women tend to have a lower
percentage of body fat than eugonadal women despite lower circulating
concentrations of leptin (73). Therefore, alterations of the gonadal
steroid milieu, whether exogenous (e.g. administration of
androgens or gonadectomy) or endogenous (e.g. puberty) would
be predicted to affect leptin sensitivity, the thresholds for
leptin-mediated effects on behavior and metabolism below which an
organism will demonstrate stigmata of leptin deficiency. Gonadal
steroid effects on leptin sensitivity thus represent a hormonally
driven sexual dimorphism in the regulation of systems regulating energy
homeostasis and response to weight change. As discussed earlier in
regard to the sexual dimorphism of body composition, the presence of
androgen and estrogen receptors in neurons comprising hypothalamic
nuclei that are involved in systems of energy homeostasis (1, 44, 45, 46)
make gonadal steroids, either directly or via effects on gonadotropin
release, strong candidate signals for changes in the sensitivity of the
central nervous system to leptin-mediated signals.
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Body composition, leptin, and fertility
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Frisch et al. (38, 39, 40) proposed that somatic fractional
fat mass played a role in mediating menarche (17% body fat) and
fertility (22% body fat) in women. The amenorrhea of women maintaining
a very low fat mass through exercise or due to illness or an eating
disorder is well known (46). Decreased fertility is an integral aspect
of the phenotypes of Lepob,
Leprdb, and Leprfa
rodents (88, 89), and the infertility of the leptin-deficient mouse
(Lepob) is corrected by the administration of
leptin (79, 90). Ovaries from the normally anovulatory
Lepob or Leprdb mouse
will ovulate if transplanted into a nonmutant female mouse (91, 92).
Thus, the infertility of the ob and db mice is
due to hypothalamic, rather than primary, ovarian dysfunction.
Although pubescence and fertility are not synonymous, leptin
administration has been shown to hasten the onset of puberty (defined
on the basis of vaginal opening size, age at first estrus, ovary
weight, ovulatory index, and uterine weight and cross-sectional area)
in pair-fed rodents (93). A prepubertal rise in the serum leptin
concentration has been proposed as a trigger for the onset of puberty
in male humans (64) via signaling of the hypothalamic-pituitary-gonadal
axis regarding the nutritional state of the organism. In addition,
administration of leptin to rodents increases sexual behavior in fed,
but not in food-deprived, female hamsters (94). These observations are
consistent with the hypothesis that leptin functions as an afferent
signal regarding somatic energy stores that influences reproductive
activity and behavior to synchronize endocrine and behavioral
components of reproductive function with the sufficiency of energy
stores. The influences of adipose tissue mass and estrogen on
circulating concentrations of leptin would signal that females were
both nutritionally and endocrinologically prepared for reproduction.
The apparent decrease in leptin sensitivity in response to increased
estrogen might function to encourage increased energy intake during
pregnancy, lactation, or periods of maximum fertility in preparation
for pregnancy.
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Perspectives
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Evolutionary pressures select for or against the prevalence genes
by affecting the likelihood of reproductive efficiency and the survival
of progeny. Longevity beyond the reproductive years should not be
subjected to such selection pressures, except insofar as having a
surviving parent increases the likelihood of the survival of existing
offspring. These principles are clearly evident in the sexual
dimorphism of body habitus between male and female humans.
Genes favoring mobility, strength to compete with other males for
mating privileges, and aggressiveness during periods of maximum
fertility (adolescence in males and estrus in females) would presumably
be selected for in males. Both genders would benefit from genes tending
to enhance the ability to store excess calories as fat. Because such a
tendency would have enabled our distant progenitors to survive periods
of prolonged caloric deficiency, it is likely that the human genome
would be heavily enriched with such genes. Survival advantages related
to genetic predisposition to storage of calories as fat would be
greater in women than in men because women are subjected to the
additional energy demands of sustaining gestation and of breastfeeding
offspring but are less subject than males to selection pressures
favoring increased strength, mobility, and aggressiveness.
Leptin integrates systems of energy homeostasis with those controlling
the hypothalamic-pituitary-gonadal axis. There are complex reciprocal
interactions of these processes so that leptin affects the integrity of
the gonadal axis, and the gonadal steroids affect both leptin
production and sensitivity. Pregnancy and lactation are examples of
periods in the life cycle when it is desirable to increase energy
intake and adipose tissue mass. Perhaps placenta-driven increases in
circulating estrogen raise the central nervous system threshold to
ambient leptin in the gravid female.
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Footnotes
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1 This work was supported by NIH Grants DK-30583, DK-52431, and
DK-26687 and General Clinical Research Center Grants RR-00047 and
RR00102. 
Received February 22, 1999.
Accepted March 16, 1999.
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References
|
---|
-
Rosenbaum M, Leibel R, Hirsch J. 1997 Medical
progress: obesity. N Engl J Med. 337:396407.[Free Full Text]
-
Kennedy G. 1953 The role of depot fat in the
hypothalamic control of food intake in the rat. Proc R Soc Biol Sci. 140:578592.
-
Rosenbaum M, Leibel R. 1998 Leptin: a molecule
integrating somatic energy stores, energy expenditure, and fertility. Trends Endorcinol Metab. 9:117123.[CrossRef]
-
Legato M. 1997 Gender-specific aspects of obesity. Int J Fertil Womens Med. 42:184197.[Medline]
-
Norgan N. 1997 The beneficial effects of body fat
and adipose tissue in humans. Int J Obesity. 21:738746.[CrossRef]
-
Rosenbaum M, Nicolson M, Hirsch J, et al. 1996 Effects of gender, body composition, and menopause on plasma
concentrations of leptin. J Clin Endocrinol Metab. 81:34243427.[Abstract]
-
Rosenbaum M, Nicolson M, Hirsch J, Murphy E, Chu F,
Leibel R. 1997 Effects of weight change on plasma leptin
concentrations and energy expenditure. J Clin Endocrinol Metab. 82:36473654.[Abstract/Free Full Text]
-
Shimizu H, Shimomura Y, Nakanishi Y, et al. 1997 Estrogen increases in vivo leptin production in rats and
human subjects. J Endocrinol. 154:285292.[Abstract]
-
Expert Panel on the Identification, Evaluation, and
Treatment of Overweight in Adults. 1998 Clinical guidelines on the
identification, evaluation, and treatment of overweight and obesity in
adults: executive summary. Am J Clin Nutr. 68:899917.[Free Full Text]
-
Gallagher D, Belmonte D, Deurenberg P, et al. 1998 Organ-tissue mass measurement allows modeling of REE and metabolically
active tissue mass. Am J Physiol. 275:E249E258.
-
Heymsfield S, Wang Z, Baumgartner R, Ross R. 1997 Human body composition: advances in models and methods. Annu Rev Nutr. 17:527558.[CrossRef][Medline]
-
Heymsfield SB, Waki M. 1991 Body composition in
humans: advances in the development of multicompartment chemicals
models. Nutr Rev. 49:97108.[Medline]
-
Heymsfield S, Lichtman S, Baumgartner R, et al. 1990 Human body composition: comparison of two improved
four-compartment models that differ in expense, technical complexity
and radiation exposure. Am J Clin Nutr. 52:5258.[Abstract]
-
Lukaski HC. 1987 Methods for the assessment of
human body composition: traditional and new. Am J Clin Nutr. 46:537556.[Abstract]
-
Pietrobelli A, Formica C, Wang Z, Heymsfield S. 1996 Dual-energy x-ray absorptiometry body composition model: review of
physical concepts. Am J Physiol. 271:E941E951.
-
Kroger H, Reeve J. 1998 Diagnosis of osteoporosis
in clinical practice. Ann Med. 30:278287.[Medline]
-
Scheiber L, Torregrosa L. 1998 Evaluation and
treatment of post-menopausal osteoporosis. Semin Arthritis Rheum. 27:245261.[Medline]
-
Pouliot M, Despres J, Lemieux S, et al. 1994 Waist
circumference and abdominal sagittal diameter: best simple
anthropometric indexes of abdominal visceral adipose tissue
accumulation and related cardiovascular risk in men and women. Am
J Cardiol. 73:460468.[Medline]
-
Rimm E, Stampfer M, Giovannucci E, et al. 1995 Body
size and fat distribution as predictors of coronary artery disease
among middle aged and older US men. Am J Epidemiol. 141:11171127.[Abstract]
-
Walker S, Rimm E, Ascherio A, Kawachi I, Stampfer M,
Willett W. 1996 Body size and fat distribution as predictors of
stroke among U.S. men. Am J Epidemiol. 144:14431450.
-
Bjorntorp P.1990 "Portal" adipose tissue as a
generator of risk for cardiovascular disease and diabetes. Arteriosclerosois. 10:493496.
-
Stromblad G, Bjorntorp P. 1986 Reduced hepatic
insulin clearance in rats with dietary induced obesity. Metabolism. 35:323327.[Medline]
-
Svedberg J, Stromblad G, Wirth A, Smith U, Bjorntorp
P. 1991 Fatty acids in the portal vein of the rat regulate hepatic
insulin clearance. J Clin Invest. 88:20542058.[Medline]
-
Lemieux S, Prudhomme D, Bouchard C, Tremblay A,
Despres J. 1993 Sex differences in the relation of visceral
adipose tissue accumulation to total body fatness. Am J Clin Nutr. 58:463467.[Abstract]
-
OBrien S, Welter B, Mantzke K, Price T. 1998 Identification of progesterone receptor in human subcutaneous adipose
tissue. J Clin Endocrinol Metab. 83:509513.[Abstract/Free Full Text]
-
Pedersen S, Fuglsig S, Sjorgen P, Richelsen B. 1996 Identification of steroid receptors in human adipose tissue. Eur J
Clin Invest. 26:10511056.[CrossRef][Medline]
-
Bjorntorp P. 1997 Hormonal control of regional fat
distribution. Hum Reprod. 12(Suppl):S21S25.
-
Pedersen S, Hansen P, Lund S, Odgaard A, Richelsen
B. 1996 Identification of oestrogen receptors and oestrogen
receptor mRNA in human adipose tissue. Eur J Clin Invest. 26:262269.[Medline]
-
Mayes J, McCann J, Ownbey T, Watson G. 1996 Regional differences and up-regulation of progesterone receptors in
adipose tissue from oestrogen-treated sheep. J Endocrinol. 148:1925.[Abstract]
-
Wilson JD, Foster DW, eds. 1992 Williams textbook
of endocrinology, 8th ed. Philadelphia: Saunders.
-
Vicennati V, Gambineri A, Calzoni F, et al. 1998 Serum leptin in obese women with polycystic ovarian syndrome is
correlated with body weight and fat distribution but not with androgen
and insulin levels. Metabolism. 47:988992.[Medline]
-
Elbers J, Asscheman M, Seidell J, Megens J, Gooren
L. 1997 Long-term testosterone administration increases visceral
fat in female-to-male transsexuals. J Clin Endocrinol Metab. 82:20442047.[Abstract/Free Full Text]
-
Lovejoy J, Bray G, Bourgeois M, et al. 1996 Exogenous androgens influence body composition and regional body fat
distribution in obese post-menopausal womena clinical research center
study. J Clin Endocrinol Metab. 81:2198203.[Abstract]
-
Lemieux S, Despres J, Moorjani S, et al. 1995 Are
gender differences in cardiovascular disease risk factors explained by
the level of visceral adipose tissue? Diabetologia. 37:757764.
-
Kotani K, Tokunaga K, Fujioka S, et al. 1994 Sexual
dimorphism of age-related whole body fat changes in the obese. Int J
Obesity. 18:207212.
-
Troisi R, Wolf A, Mason J, Klinger K, Colditz G. 1995 Relationship of body fat distribution to reproductive factors in
pre- and postmenopausal women. Obesity Res. 3:143151.[Abstract]
-
Lobo M, Remesar X, Alemany M. 1993 Effect of
chronic intravenous injection of steroid hormones on body weight and
composition of female rats. Biochem Mol Biol Int. 29:349358.[Medline]
-
Frisch R, Revelle R. 1970 Height and weight at
menarche and a hypothesis of critical body weights and adolescent
events. Science. 169:397399.[Medline]
-
Frisch R. 1985 Fatness, menarche, and female
fertility. Perspect Biol Med. 28:611633.[Medline]
-
Frisch R. 1987 Body fat, menarche, fitness, and
fertility. Hum Reprod. 2:521533.[Abstract]
-
Goldsmith P, Boggan J, Thind K. 1997 Estrogen and
progesterone receptor expression in the neuroendocrine and related
neurons of the pubertal female monkey hypothalamus. Neuroendocrinology65
:325334.
-
Osterlund M, Kuiper G, Gustafsson J, Hurd Y. 1998 Differential regulation of estrogen receptor
- and ß-mRNA within
the female rat brain. Brain Res Mol Brain Res. 54:175180.[Medline]
-
McAbee M, DonCarlos L. 1998 Ontogeny of
region-specific sex differences in androgen receptor messenger
ribonucleic acid expression in the rat forebrain. Endocrinology. 139:17381745.[Abstract/Free Full Text]
-
Greco B, Edwards D, Zumpe D, Clancy A. 1998 Androgen receptor and mating-induced Fos immunoreactivity are
co-localized in limbic and midbrain neurons that project to the male
rat medial preoptic area. Brain Res. 781:1524.[CrossRef][Medline]
-
Choate J, Slayden O, Resko J. 1998 Immunocytochemical localization of androgen receptors in brains of
developing and adult rhesus monkeys. Endocrinology. 8:5160.
-
Wade G, Schneider J, Li H. 1996 Control of
fertility by metabolic cues. Am J Physiol. 270:E1E19.
-
Maffei M, Halaas J, Ravussin E, et al. 1995 Leptin
levels in human and rodents: measurement of plasma leptin and
ob RNA in obese and weight-reduced subjects. Nat Med. 1:11551161.[Medline]
-
Eckert E, Pomeroy C, N NR, Thuras P, Bowers C. 1998 Leptin in anorexia nervosa. J Clin Endocrinol Metab. 83:791795.[Abstract/Free Full Text]
-
Licinio J, Negrao A, Mantzoros C, et al. 1998 Sex
differences in circulating human leptin pulse amplitude: clinical
implications. J Clin Endocrinol Metab. 83:41404147.[Abstract/Free Full Text]
-
Montague CT, Prins JB, Sanders L, Digby JE, ORahilly
S.1997 Depot- and sex-specific differences in human leptin mRNA
expression: implications for the control of regional fat distribution. Diabetes. 46:342347.
-
Harmelen VV, Reynisdottir S, Erikkson P, et al. 1998 Leptin secretion from subcutaneous and visceral adipose tissue in
women. Diabetes. 47:913917.[Abstract]
-
Nagy T, Bower G, Trowbridge C, Dezenberg C, Shewchuk R,
Goran M. 1997 Effects of gender, ethnicity, body composition, and
fat distribution on serum leptin levels in children. J Clin
Endocrinol Metab. 82:21482152.[Abstract/Free Full Text]
-
Hube F, Lietz U, Igel M, et al. 1996 Differences in
leptin mRNA levels between omental and subcutaneous adipose tissue from
obese humans. Horm Metab Res 28:690693.
-
Leenen R, Kooy Kvd, Deurenberg P, et al. 1992 Visceral fat accumulation in obese subjects: relation to energy
expenditure and response to weight loss. Am J Physiol.
263:E913E919.
-
Deleted in proof.
-
Montague C, Prins J, Sanders L, Digby J, ORahilly
S. 1997 Depot- and sex-specific differences in human leptin mRNA
expression: implications for the control of regional fat distribution. Diabetes. 46:342347.[Abstract]
-
Matsuda J, Yokota I, Iida M, et al. 1997 Serum
leptin concentrations in cord blood: relationship to birthweight and
gender. J Clin Endocrinol Metab. 82:16421644.[Abstract/Free Full Text]
-
Ellis K, Nicolson M. 1997 Leptin levels and body
fatness in children: effects of gender, ethnicity, and sexual
development. Pediatr Res. 42:484448.[Abstract]
-
Arslanian S, Suprasongsin C, Kalhan S, Drash A, Brna R,
Janosky J. 1998 Plasma leptin in children: relationship to
puberty, gender, body composition, insulin sensitivity, and energy
expenditure. Metabolism. 47:309312.[Medline]
-
Argente J, Barrios V, Chowen J, Sinha M, Considine
R. 1997 Leptin levels in healthy Spanish children and adolescents,
children with obesity, and adolescents with anorexia nervosa and
bulimia nervosa. J Pediatr. 131:833838.[Medline]
-
Troen P, Oshima H. 1981 The testis. In: Felig P,
Baxter J, Broadus A, Frohman L, eds. Endocrinology and metabolism. New
York: McGraw-Hill; 627668.
-
Speroff L. 1981 The ovary. In: Felig P, Baxter J,
Broadus A, Frohman L, eds. Endocrinology and metabolism. New York:
McGraw-Hill; 669724.
-
Roemmich J, Clark P, Berr S, et al. 1998 Gender
differences in leptin levels during puberty are related to the
subcutaneous fat depot and sex steroids. Am J Physiol.
275:E543E551.
-
Mantzoros C, Dunaif A, Flier J. 1997 Leptin
concentrations in the polycystic ovary syndrome. J Clin Endocrinol
Metab. 82:16871691.[Abstract/Free Full Text]
-
Clayton P, Gill M, Hall C, Tillman V, Whatmore A, Price
D. 1997 Serum leptin through childhood and adolescence. Clin
Endocrinol (Oxf). 46:737733.
-
Jockenhovel F, Blum W, Vogel E, et al. 1997 Testosterone substitution normalizes elevated serum leptin levels in
hypogonadal men. J Clin Endocrinol Metab. 82:25102513.[Abstract/Free Full Text]
-
Wabitsch M, Blum W, Muche R, et al. 1997 Contribution of androgens to the gender difference in leptin production
in obese children and adolescents. J Clin Invest. 100:808813.[Abstract/Free Full Text]
-
Haffner S, Miettinen H, Karhapaa P, Mykkanen L, Laasko
M. 1997 Leptin concentrations, sex hormones, and cortisol in
nondiabetic men. J Clin Endocrinol Metab. 82:18071809.[Abstract/Free Full Text]
-
Casebielli X, Pineiro V, Peino R, et al. 1998 Gender differences in both spontaneous and stimulated leptin secretion
by human omental adipose tissue in vitro: dexamethasone and
estradiol stimulated leptin release in women, but not men. J Clin
Endocrinol Metab. 83:21492155.[Abstract/Free Full Text]
-
Paolisso G, Rizzo M, Mone C, et al. 1998 Plasma sex
hormones are significantly associated with plasma leptin in healthy
subjects. Clin Endocrinol (Oxf). 48:291297.[CrossRef][Medline]
-
Perry H, Morley J, Horowitz M, Kaiser F, Miller D,
Wittert G. 1997 Body composition and age in african-american and
caucasian women: relationship to plasma leptin levels. Metabolism. 46:13991405.[Medline]
-
Ambrosius W, Compton J, Bowsher R, Pratt J. 1998 Relationship of race, age, and sex hormone differences to serum leptin
concentrations in children and adolescents. Horm Res. 49:240246.[CrossRef][Medline]
-
Elbers J, Asscheman H, Seidell J, Frolich M, Meinders A,
Gooren L. 1997 Reversal of the sex difference in serum leptin
levels upon cross-sex hormone administration in transsexuals. J
Clin Endocrinol Metab. 82:32673270.[Abstract/Free Full Text]
-
Chapman I, Wittert G, Norman R. 1997 Circulating
leptin concentrations in polycystic ovary syndrome: relationship to
anthropometric and metabolic parameters. Clin Endocrinol (Oxf). 46:175181.[Medline]
-
Laughlin G, Morales A, Yen S. 1997 Serum leptin
levels in women with polycystic ovary syndrome: the role of insulin
resistance/hyperinsulinemia. J Clin Endocrinol Metab. 82:16921696.[Abstract/Free Full Text]
-
Mantzoros C, Flier J, Rogol A. 1997 A longitudinal
assessment of hormonal and physical alterations during normal puberty
in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab. 82:10661070.[Abstract/Free Full Text]
-
Rouru J, Anttila L, Koskinen P, et al. 1997 Serum
leptin concentrations in women with polycystic ovary syndrome. J
Clin Endocrinol Metab. 82:1697700.[Abstract/Free Full Text]
-
Leibel RL, Chung WK, Chua SC. 1997 The molecular
genetics of rodent single gene obesities. J Biol Chem. 272:3193731940.[Free Full Text]
-
Ahima RS, Prabakaran D, Mantzoros C, et al. 1996 Role of leptin in the neuroendocrine response to fasting. Nature. 382:250252.[CrossRef][Medline]
-
Larsson H, Elmstahl S, Berglund G, Ahern B. 1998 Evidence of leptin regulation of food intake in humans. J Clin
Endocrinol Metab. 83:43824385.[Abstract/Free Full Text]
-
Salbe A, Nicolson M, Ravussin E. 1997 Total energy
expenditure and physical activity correlate with plasma leptin
concentrations in five-year-old children. J Clin Invest. 99:592595.[Abstract/Free Full Text]
-
Tuominen J, Ebeling P, Heiman M, Stephens T, Koivisto
V. 1997 Leptin and thermogenesis in humans. Acta Physiol Scand. 160:8387.[Medline]
-
Toth M, Gottlieb S, Fisher M, Ryan A, Nicklas B,
Poehlman E. 1997 Plasma leptin concentrations and energy
expenditure in heart failure patients. Metabolism. 46:450453.[Medline]
-
Kennedy A, Gettys T, Watson P, et al. 1997 The
metabolic significance of leptin in humans: gender-based differences in
relationship to adiposity, insulin-sensitivity, and energy expenditure. J Clin Endocrinol Metab. 82:12931300.[Abstract/Free Full Text]
-
Niskanen L, Haffner S, Karhunen L, Turpeinen A,
Miettinen H, Uusitupa M. 1997 Serum leptin in relation to resting
energy expenditure and fuel metabolism in obese subjects. Int J
Obesity. 21:309313.[CrossRef]
-
Leibel R, Rosenbaum M, Hirsch J. 1995 Changes in
energy expenditure resulting from altered body weight. N Eng
J Med. 332:621628.[Abstract/Free Full Text]
-
Maffei M, Halaas J, Ravussin E, et al. 1996 Leptin
levels in human and rodent: measurement of plasma leptin and
ob RNA in obese and weight-reduced subjects. Nat Med. 1:11551161.
-
Mounzih K, Lu R, Chehab F. 1997 Leptin rescues the
sterility of genetically obese ob/ob males. Endocrinology. 138:11901193.[Abstract/Free Full Text]
-
Coleman DL. 1978 Obese and diabetes: two mutant
genes causing diabetes-obesity syndromes in mice. Diabetologia. 14:141148.[Medline]
-
Chehab F, Lim M, Lu R. 1996 Correction of the
sterility defect in homozygous obese female mice by treatment with the
human recombinant leptin. Nat Genet. 12:318320.[Medline]
-
Friedman J, Leibel R, Bahary N. 1991 Molecular
mapping of obesity genes. Mamm Genom. 1:130144.
-
Spicer L, Francisco C. 1997 The adipose obese gene
product, leptin: evidence of a direct inhibitory role in ovarian
function. Endocrinology. 138:33743379.[Abstract/Free Full Text]
-
Cheung C, Thornton J, Kuijper J, Weigle D, Clifton D,
Steiner R. 1997 Leptin is a metabolic gate for the onset of
puberty in the female rat. Endocrinology. 138:855858.[Abstract/Free Full Text]
-
Wade B, Lempicki R, Panicker A, Frisbee R, Blaustein
J. 1997 Leptin facilitates and inhibits sexual behavior in female
hamsters. Am J Physiol. 272:R1354R1358.