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Original Studies |
Department of Pediatrics, Columbia University College of Physicians and Surgeons (M.B.H., M.R., R.L.L., L.S.L.), New York, New York 10032; Body Composition Unit, St. Luke’s/Roosevelt Hospital Center (J.W., B.F., R.N.P.) New York, New York 10019; and Amgen Inc. (M.N.), Thousand Oaks, California 91320-1789
Address correspondence and requests for reprints to: Michael Rosenbaum, M.D., Division of Molecular Genetics, Russ Berrie Medical Science Pavilion and Naomi Berrie Diabetes Center, 1150 St. Nicholas Avenue, New York, New York 10032. E-mail: mr475{at}columbia.edu
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Abstract |
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Pubertal stage was assigned by physical examination (Tanner staging) and also assessed by measurement of plasma estradiol, testosterone, and pituitary gonadotropins. Body composition was determined by dual-energy x-ray absorptiometry and by anthropometry. Circulating concentrations of leptin in the postabsorptive state were determined by a solid-phase sandwich enzyme immunoassay. The effect of gender on the relationship between circulating leptin concentrations and FM was determined by ANOVA at each Tanner stage. Stepwise multiple linear regression analyses, including circulating concentrations of pituitary-gonadal axis hormones, and FM were performed, by gender, to determine whether the relationship between circulating concentrations of leptin and FM changes during puberty.
Plasma leptin concentrations were significantly correlated with FM at all Tanner stages in males and females. Plasma leptin concentrations, normalized to FM, were significantly higher in females than males at Tanner stages IV and V but not at earlier stages of pubertal development. Plasma leptin concentrations, normalized to FM, were significantly greater in females at Tanner stage V compared with females at Tanner stage I and significantly lower in males at Tanner stage IV and V compared with males at Tanner stage I. These significant gender and maturational differences were confirmed by demonstrating that the regression equation relating circulating leptin concentrations to FM in females and males at Tanner stages IV and V were significantly different (predicted lower leptin concentrations in males than females with identical body composition) and that the regression equations relating circulating concentrations of leptin to FM in each gender before puberty (Tanner stage I) were significantly different (predicted higher plasma concentrations of leptin in prepubertal males and lower leptin concentrations in prepubertal females) than the same regression equations in later puberty. Circulating concentrations of testosterone were significant negative correlates of circulating concentrations of leptin normalized to FM in males when considered as a group over all pubertal stages. The inclusion in multivariate regression analyses of circulating concentrations of testosterone and estradiol, FM, fat-free mass, and gender did not eliminate a significant gender-effect (P < 0.05) on circulating concentrations of leptin at Tanner stages IV and V.
The circulating concentration of leptin, normalized to FM, declines significantly in males and rises significantly in females late in puberty to produce a late-pubertal/adult sexual dimorphism. These studies confirm a potent role for gonadal steroids as mediators of this sexual dimorphism in circulating concentrations of leptin. The persistence of a significant gender-effect on circulating leptin concentrations at Tanner stages IV and V, even when the regression equation includes body composition and circulating concentrations of gonadal steroids, however, suggests that this sexual dimorphism also reflects the direct or interactive effects of either other sex-related metabolic variables (such as insulin, GH, or body fat distribution) or additional X or Y- chromosome-linked gene effects that produce an increasing sexual dimorphism of circulating leptin concentrations later in puberty.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We examined body composition by dual-energy x-ray absorptiometry (DEXA) and anthropometry, pituitary-gonadal axis hormones, and circulating concentrations of leptin in a cross-sectional study of children at Tanner stages I–V to assess the sex-specific relationship between leptin and FM at all stages of puberty.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We recruited 102 subjects (53 males and 49 females; 61 Caucasian
Americans, 18 African Americans, 11 Hispanic Americans, 1 Asian
American, and 11 others) by advertisement. This study was approved by
the Institutional Review Board of St. Luke’s/Roosevelt Hospital Center
(New York, NY). Parental consent was obtained from all subjects who
also gave their assent to participate. All subjects were in good health
and taking no chronic medications. Pubertal stage was assigned by
physical examination by a single investigator (MBH), according to the
criteria of Tanner for breast development in females and genital
development in males (37), and also assessed as a
continuous variable using the measurement of serum concentrations of
estradiol, testosterone, and gonadotropins (LH and FSH) (38, 39). No attempt was made to control for stage of menstrual cycle
in postmenarchal females. However, Demerath et al.(15) have reported no significant effects of
variation in stages of the menstrual cycle on circulating
concentrations of leptin in postmenarchal females. All biochemical
tests and measures of body composition were obtained in the
postabsorptive state (in the morning between 0800 and 1000 h
following an overnight fast). Subject characteristics are presented in
Table 1
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Body weight was measured to the nearest 0.1 kg (Weight Tronix, New York, NY), and height was measured to the nearest millimeter using a wall-mounted stadiometer (Holtain, Crosswell, Wales). Skinfold thicknesses (subscapular, chest, thorax, abdominal and suprailiac, biceps, triceps, thigh, and medial calf) in millimeters were measured using a Lange skinfold caliper (Lange, Cambridge, MD) on the right side of the body by two cross-trained observers (40).
Body composition was determined by DEXA (41) using a Lunar model DPX with pediatric software 3.8 G (Lunar Co., Madison, WI) (42). The scanning time varied with subject height. Each scan provided measurements of fat-free mass (FFM) and FM in kilograms. The repeat measurements variability in measuring FM in adult subjects by DEXA in our laboratory is 3.3% (42, 43).
Assays
Postabsorptive plasma leptin concentrations were assayed by a solid-phase sandwich enzyme immunoassay using an affinity-purified polyvalent antibody immobilized in microliter wells (Margery Nicolson, Amgen Inc., Torrance, CA). Bound leptin was detected with affinity-purified antibody conjugated to horseradish peroxidase and quantified with a chromogenic substrate (TMB/peroxide). Leptin concentrations were calculated from standard curves generated for each assay using recombinant human leptin. Minimal detectable leptin is 20 pg/mL (2). Serum concentrations of testosterone and estradiol were determined by RIA, and serum concentrations of LH and FSH were determined by immunochemoluminometric assay (Endocrine Sciences, Calabasas Hills, CA).
Statistical analyses
Standard multiple stepwise linear regression was used to
facilitate comparisons of our results with other studies that have used
this type of analysis (34). Forward stepwise linear
regression (F to enter = 1.00, F to remove = 0.00) analyses
were used to determine effects of gonadal axis maturation (circulating
concentrations of testosterone and estradiol), total skinfold
thicknesses or body composition (FM and FFM as determined by DEXA), and
gender (defined as a dichotomous variable; male = 1; female =
2) as independent variables on circulating concentrations of leptin
(dependent variable). Subjects who were clinically at Tanner stages II
or III were considered as a single early-pubertal group after it became
apparent that there were no trends toward any differences in the
relationship of body composition to circulating concentrations of
leptin between males or females at Tanner stages II or III (see Fig. 1). Total skinfold thicknesses were
entered into regression equations containing testosterone, estradiol,
FFM, and gender to test the hypothesis of Roemmich et al.
(34) that gender differences in circulating leptin
concentrations during puberty are accounted for largely by the sc fat
depot, FM, and sex steroids, and that measures of total skinfold
thicknesses are better correlates of leptin than total FM. Between
groups, comparisons were made by one-way ANOVA.
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). For
a female with a relatively high FM (25 kg), this regression equation
predicts a circulating leptin concentration of 33.5 ng/mL and a leptin
to FM ratio of 1.3 ng/mL·kg. For a female with a relatively low FM
(15 kg), the regression equation predicts a circulating leptin
concentration of leptin of 5.5 ng/mL and a leptin to FM ratio of 0.4
ng/mL·kg. Therefore, even though the relationship between leptin and
FM in both of these hypothetical cases is described by the same
regression equation, if one were to express data only as the ratio of
leptin to FM, one might incorrectly conclude (due to the non-zero
intercept of the regression line) that heavier women had a different
relationship of circulating concentrations of leptin to FM than less
obese women.
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Adjusted cell means of circulating leptin concentrations for all males and females and for males and females at each Tanner stage were calculated from an analysis of covariance in which gender was the grouping variable, leptin was the dependent variable, and FM, FFM, testosterone, and estradiol were covariates.
All analyses were performed on a Dell Dimension XPS M200 PC using the
Statistica (Statsoft, Tulsa, OK) statistical analysis package, version
5.1 (44). Statistical significance was prospectively
defined as P
< 0.05. Statistically
significant equations, correlation coefficients, and P
values are reported in bold. In multiple stepwise regression
analyses, covariates dropped by the forward stepwise linear regression
analyses are not reported.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Plasma leptin concentrations were
significantly correlated with FM at all Tanner stages in males and
females (Table 2). The addition of FFM to the regression equations
improved the fraction of variance in circulating concentrations of
leptin accounted for by forward stepwise linear regression analysis at
Tanner stages II and III, IV, and V in males and Tanner stages IV and V
in females (Table 2A
). In multiple linear regression analyses treating
plasma leptin as the dependent variable and FM, gonadal steroid
concentrations, and gender (entered as a dichotomous variable:
male = 1; female = 2) as independent variables, gender was
significantly related to plasma leptin concentrations only at Tanner
stages IV and V (partial r = 0.53, P = 0.006)
(Table 2A). In all multiple linear regression analyses, which included
subjects at multiple Tanner stages, a greater proportion of the
variance was explained by regressions, including gonadal steroid
concentrations as an index of pubertal development compared with the
same regression using clinical Tanner stage (analyses not shown) as a
covariate instead of gonadal steroids. Furthermore, in forward stepwise
linear regression analyses relating circulating concentrations of
leptin to all variables (FM, FFM, skinfold, testosterone, estradiol,
and gender), skinfold thicknesses were always dropped from the final
equation (i.e. there is no evidence that skinfold
thicknesses have any detectable effect on the variance in circulating
concentrations of leptin once corrected for the other variables; Table 2A).
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We repeated the analysis of Roemmich et al.
(34) and found no significant gender effect on circulating
leptin concentrations corrected for testosterone, estradiol, and total
skinfold thicknesses if children from Tanner stages II–V were
considered as a group (Table 2B). There was no instance in which a
greater proportion of the variance in the circulating concentration of
leptin was accounted for by using skinfold thicknesses and FFM as
independent variables as compared with FM and FFM (Table 2A). A
significant sexual dimorphism (females > males) in circulating
concentrations of leptin was still noted using the sum of skinfold
thicknesses (representing sc adipose tissue) as an indicator of FM
(Table 2B) instead of absolute total adipose tissue mass (Table 2A). It
is clear (Table 1) that females at Tanner stages IV and V have
significantly greater sc adipose tissue thickness than males at the
same Tanner stages. To determine whether this sexual dimorphism in
partitioning of fat to sc vs. visceral adipose tissue depots
could account for the sexual dimorphism in circulating leptin
concentrations, a standard stepwise linear regression analysis was
performed in which leptin concentrations at Tanner stages IV and V was
the dependent variable and FM, FFM, skinfold thicknesses, gonadal
steroid concentrations, and gender were the independent variables.
Skinfold thickness was not a significant covariate of the circulating
leptin concentrations in this analysis, but the significant gender
effect remained, indicating that the relatively greater partitioning of
fat in sc vs. visceral adipose tissue in Tanner stage IV and
V females did not account for a significant proportion of the sexual
dimorphism in circulating leptin concentrations.
In regression equations in which adipose tissue mass was the dependent
variable and the sum of skinfold thicknesses and circulating
gonadotropins were independent variables, circulating concentration of
estradiol was a significant covariate of adipose tissue mass in females
(P = 0.01) but not in males. No significant effect of
circulating concentrations of testosterone on this relationship was
noted in either gender (Table 3).
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). This difference was not due to a non-zero intercept
of the regression equation relating leptin to FM because residual
concentrations of leptin calculated for Tanner stage V females using
the regression equation relating plasma leptin concentration to FM in
Tanner stage I females were significantly greater than zero. In males,
the ratios of circulating concentrations of leptin to FM were
significantly lower at Tanner stages IV and V than at Tanner stages I,
II, or III (Fig. 1). This difference was not due to a non-zero
intercept of the regression equation relating leptin to FM because
residual concentrations of leptin calculated for Tanner stages IV and V
males using the regression equation relating plasma leptin
concentrations to FM in Tanner stage I males were significantly less
than zero (Table 4).
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). This difference was not due to a
non-zero intercept of the regression equation relating leptin to FM
because residual concentrations of leptin calculated using the
regression equation relating circulating concentrations of leptin to FM
in males at the same Tanner stage were significantly greater than zero
only at Tanner stages IV and V. In addition, adjusted cell means for
circulating concentrations of leptin were significantly greater in
females than males only at Tanner stages IV and V (Tables 4 and 5). Similarly, significant negative
residuals of circulating leptin concentrations in males were noted at
Tanner stages IV and V using the regression equation relating
circulating concentrations of leptin to FM in females at the same
Tanner stage (data not shown).
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). Serum
concentrations of estradiol were significantly correlated with serum
concentrations of LH (r2 = 0.56, P <
0.0001) and FSH (r2 = 0.25, P =
0.0003) in females. As expected, serum concentrations of testosterone
were significantly correlated with serum concentrations of LH
(r2 = 0.50, P < 0.0001) and FSH
(r2 = 0.26, P < 0.0001) in males
(Table 1). Despite the significant correlations between serum
concentrations of gonadotropins and testosterone and between serum
testosterone concentrations and ratios of plasma concentrations of
leptin to FM in males, no significant correlation between gonadotropins
and circulating concentrations of leptin normalized to FM were noted
(data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The observation that there is a significant sexual dimorphism in circulating leptin concentrations at Tanner stage IV (prior to a significant increase in circulating leptin concentrations per unit of FM in females, but at the same time that there is a significant decrease in this measure in males) suggests that the higher concentrations of leptin normalized to FM observed in female adults (2, 4, 5, 6, 7) are due both to suppression of leptin messenger RNA expression and leptin secretion by androgens in males and to estrogen-mediated augmentation of leptin secretion in females. Androgen-mediated leptin suppression of leptin secretion occurs in males at Tanner stage IV. Later in puberty (Tanner stage V, after androgen-induced suppression of leptin in males has already become evident), estrogen-mediated augmentation of circulating concentrations of leptin in late pubertal females further augments the sexual dimorphism in circulating leptin concentrations. Ahmed et al.(45) reported that girls continued to show increases in their serum leptin concentrations with age even beyond Tanner stage V and also suggest that estrogen augments serum leptin levels.
Some studies have reported that the same degree of sexual dimorphism in circulating leptin concentrations is present in neonates (27, 46, 47), whereas others have noted no gender effects on circulating concentrations of leptin in neonates (48, 49). In cord blood, Matsuda et al. (27) reported no significant differences between male and female neonatal concentrations of testosterone and estradiol, but noted approximately 2-fold higher leptin concentrations in females. However, Ertl et al. (50) reported that circulating concentrations of leptin in males and females at birth were negatively correlated with neonatal testosterone concentrations. The observed sexual dimorphism of leptin concentrations in cord blood may reflect the effects of either primary genetic determinants or the prenatal sexual dimorphisms in androgen concentrations (male > female), which begin in the second trimester of gestation (38, 39). Helland et al. (51) reported that women carrying female fetuses have higher circulating concentrations of leptin than women carrying male fetuses. Tome et al. (47) noted that neonatal cord leptin concentrations were also affected by placental weight and that both placental weight and circulating leptin concentrations were higher in female neonates. Because it is not possible to distinguish the origins of neonatal leptin (maternal, placental, or fetal), it is also possible that any neonatal sex differences in circulating leptin concentrations are due to different maternal or placental production rates (52, 53).
A sexual dimorphism in the effects of puberty on circulating concentrations of leptin was also found by Carlsson et al. (33), who noted that circulating concentrations of leptin, not corrected for FM, rose during puberty in females but not in males, and by Blum et al. (32), who reported that circulating concentrations of leptin normalized to BMI rose significantly to a maximum at Tanner stage V in girls and declined to a minimum at Tanner stage V in boys.
In the present study, and contrary to the data of Roemmich et
al. (34), gender remained a significant covariate of
circulating concentrations of leptin in pubertal males and females even
when adjusted for FM, skinfold thicknesses, and gonadal steroid
concentrations (Table 2B). Roemmich et al. (34)
looked for significant gender effects on circulating concentrations of
leptin corrected for skinfold thicknesses and gonadal steroid
concentrations in prepubertal subjects vs. subjects at
Tanner stages II–V. Our data indicate that the inclusion of subjects
in early puberty (Tanner stages II and III), as in the analysis by
Roemmich et al. (34) masks a significant,
unexplained sexual dimorphism that is not evident until later
puberty.
Argente et al. (36) found that circulating concentrations of leptin, not corrected for FM, rose in males and females from Tanner stages I–III but fell significantly in males at Tanner stages IV and V while continuing to rise in females, so that a significant sexual dimorphism in circulating leptin concentrations (females > males) was achieved at Tanner stage V. In a longitudinal study of eight males, Mantzoros et al. (54) also noted an early pubertal rise in circulating leptin, followed by a decline. Similarly, Lahlou et al. (55) reported that sexual dimorphism in circulating concentrations of leptin (both at usual weight and during active weight gain) was not evident until later puberty. Wabitsch et al. (56) reported an inverse relationship between circulating concentrations of testosterone and the ratio of leptin to BMI in boys, but not girls. The same group also reported that incubation of primary adipocytes with testosterone or dihydrotestosterone was associated with significant declines in rates of leptin messenger RNA expression and leptin peptide release (56). In contrast, Arslanian et al. (57) found no differences in the relationship of circulating concentrations of leptin to FM between males and females (prepubertal and pubertal). This apparent discrepancy with our findings may be due to the fact that Arsalanian et al. (57) neither included Tanner stage V subjects in their study population nor analyzed their "late" pubertal (Tanner stage IV) subjects as a separate group from earlier pubertal stages.
The presence of sexual dimorphism in circulating leptin concentrations
in prepubertal children (which was not noted in the present study)
would support the view that there is a primary gender difference in
leptin physiology, not accounted for by circulating gonadal steroid
concentrations. In contrast to the present study, Ellis and Nicolson
(58) reported that the ratios of circulating concentration
of leptin to FM were significantly greater in females than males at
Tanner stages I, III, IV, and V. However, the Tanner stage I males in
the study by Ellis et al. (58) had an
approximately 40% lower FM than Tanner stage I females. As discussed
previously, regression lines relating circulating leptin concentrations
to FM have non-zero intercepts (Table 2). Application of the regression
equation relating circulating concentrations of leptin to FM for all
Tanner stage I subjects in our study [leptin = 1.16 - 3.7
FM (kg), r2 = 0.71, P < 0.0001] to
the data of Ellis et al. (58) illuminates this
problem. Ellis et al. (58) report mean FMs in
Tanner stage I males (4.7 kg) and in Tanner stage I females (6.5 kg).
Predicted circulating concentrations of leptin for these FMs based on
our Tanner stage I regression equation would be 1.7 ng/mL in males and
3.8 ng/mL in females. Assuming that these were the measured values, the
ratio of leptin to FM would be approximately 0.36 ng/mL·kg in males
and 0.58 ng/mL·kg in females. Assuming that males and females fall on
the same regression line relating plasma leptin concentrations to FM,
the predicted female to male ratio in concentrations of leptin per unit
of FM is 1.5 at these low FMs. This is similar to the ratio of 1.6
reported by Ellis et al. (58). Thus, the
seemingly significant gender difference in the ratio of circulating
concentrations of leptin to FM in early puberty reported by Ellis
et al. (58) may be an artifact of the non-zero
intercept of the regression line relating leptin to FM.
Demerath et al. (15) reported a significant sexual dimorphism in circulating leptin concentrations adjusted for total body fat (females > males) in prepubertal children, which increased further during puberty and postpuberty. Unlike the study by Ellis et al. (58), mean total body fat in prepubertal males was approximately 40% higher in males (8.2 ± 3.7 kg) than in females (5.9 ± 2.2 kg). Application of our prepubertal regression equations relating leptin to FM in the population reported by Demerath et al. (15) does not, therefore, suggest any artifact influencing the prepubertal sexual dimorphism in circulating leptin concentrations. The detection of this sexual dimorphism in prepubertal children by Demerath et al. (15) may be due to the larger sample of Tanner stage I males and females in that study: 29 males and 27 females vs. 13 males and 15 females in the present study. The observation of a significant sexual dimorphism in circulating leptin concentrations before puberty supports the data in the present study, which suggest that factors other than gonadal steroids may account for some of the gender difference in circulating leptin.
Leptin secretion is pulsatile, and pulse frequencies and amplitudes at each pubertal stage were not measured in this study. However, ultraradian periodicities in leptin secretion detected by Fourier analysis are similar in adult men and women (59), and the major gender-related differences in leptin secretion in adults seem to be due to pulse amplitude rather than frequency (60). Most studies of the sexual dimorphisms in circulating leptin concentrations have focused on postabsorptive concentrations. However, it is possible that that puberty influences pulse frequency as well as amplitude. Alterations in either of these parameters, as well as possible changes in leptin-clearance rates (i.e., gender-effects similar to those seen in the metabolism of growth hormone) (61), could also play a role in observed sexual dimorphism in circulating leptin concentrations.
After adjustment for effects of circulating gonadal steroid
concentrations, sc fat content, and body composition, circulating
concentrations of leptin were still significantly higher in late
pubertal females than males (Table 5). This difference suggests that
factors besides gonadal steroids, fat distribution (sc vs.
visceral), and body composition cause the sexual dimorphism in
circulating leptin concentrations that is apparent in late puberty.
Candidates for these "factors" include a primary effect of genes on
the X or Y chromosomes or other metabolic or hormonal variables
affecting circulating leptin concentrations that were not quantified in
this study (e.g. insulin, GHs, glucocorticoids, or
catecholamines) (24). Knowledge of these factors, and the
mechanisms by which they act, may enable the therapeutic manipulation
of endogenous leptin production.
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Footnotes |
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Received December 20, 1999.
Revised March 21, 2000.
Accepted March 21, 2000.
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References |
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