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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3339-3345
Copyright © 2003 by The Endocrine Society

Changes in Circulating Leptin, Leptin Receptor, and Gonadal Hormones from Infancy until Advanced Age in Humans

David R. Mann, Abiodun O. K. Johnson, Terry Gimpel and V. Daniel Castracane

Cooperative Reproductive Science Research Center and Department of Physiology, Morehouse School of Medicine (D.R.M.), Atlanta, Georgia 30310; and Departments of Obstetrics and Gynecology (T.G., V.D.C.) and Pediatrics (A.O.K.J.), Texas Tech University Health Sciences Center, Amarillo, Texas 79106

Address all correspondence and requests for reprints to: David R. Mann, Ph.D., Cooperative Reproductive Science Research Center, Department of Physiology, 720 Westview Drive SW, Atlanta, Georgia 30310.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We determined developmental changes in circulating levels of the soluble leptin receptor (sOB-R), leptin, and gonadal hormones in human subjects. In both sexes the rise in leptin with age was associated with a decline in sOB-R, and age-related changes in both parameters preceded the pubertal rise in gonadal hormones. Leptin levels above 10 ng/ml were a strong predictor of sOB-R concentrations, but this predictive value decreased as leptin declined. In young subjects there were no gender differences in serum leptin, but boys had higher sOB-R levels. In adults neither leptin nor sOB-R changed with age, but serum leptin was higher and sOB-R was lower in women than men. There was a significant negative correlation between sOB-R and leptin in women, but not men. The data suggest that bioavailable leptin in the circulation may be increasing more rapidly during development than indicated by total leptin levels, and that these changes may serve as one of the signals to the central nervous system that metabolic conditions are adequate to support pubertal development. Furthermore, the study provides suggestive evidence that leptin regulates the secretion of its own binding protein, but it also appears that an additional gender-specific, leptin-independent, regulatory mechanism is functional before puberty.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ACHIEVEMENT OF a critical body weight or fat mass is thought to play a prominent role in the initiation of puberty (1), but what metabolic factor(s) acts to signal the reproductive axis that sexual development may proceed or the means by which this signal is transmitted to this axis has not been fully delineated. Leptin has been proposed as a physiological link between nutritional status and reproductive maturation and function and may potentially serve as a trigger or metabolic gate for sexual development (2, 3, 4). Although the current consensus appears to hold that a threshold level of leptin is necessary to allow puberty to proceed, it does not appear that leptin serves as a trigger for this process (3, 4, 5, 6, 7, 8).

Spontaneous mutations of the obese gene (ob) or the gene that codes for the leptin receptor (db) are associated with hyperphagia, obesity, and infertility in mice (9, 10, 11) and humans (12, 13). The infertility can be reversed with recombinant leptin replacement therapy (10, 14). Moreover, underfeeding mice and malnutrition in humans lower leptin secretion and delay the onset of puberty (15, 16, 17, 18). These conditions in rodents can also be corrected by leptin treatment (15, 16). In humans (19), there is a progressive rise in leptin secretion during development that culminates in the achievement of reproductive competence. In girls, leptin levels in the circulation rise progressively from 5 to 15 yr of age, whereas in boys, levels increased between 5 and 10 yr of age and declined thereafter through 13 yr of age (19). In 8 prepubertal boys (Tanner’s stage 1 or early 2), serum leptin concentrations were near or at peak levels at the time of initiation of the pubertal rise in serum testosterone and testicular volume, although the magnitude of the prepubertal rise in leptin levels in half of these boys was not robust (20). Furthermore, in another study leptin values did not change with pubertal stage in boys, nor was there a transient increase in leptin before the onset of puberty (21). Thus, leptin’s role in human pubertal development has not been fully resolved.

Another unresolved issue relates to developmental changes in leptin binding, its potential role in the regulation of leptin bioavailability and how changes in leptin binding during development might impact on the process of pubertal development in humans. The leptin receptor is a member of the class I cytokine receptor family, and it exists in a number of alternatively spliced isoforms (22). The full-length form of the receptor (OB-Rb) is the only isoform that possesses all of the components needed for full cellular signaling, although other isoforms may have some signaling capacity (23). A truncated, soluble isoform of the receptor (sOB-R; corresponding to the receptor’s extracellular domain) is secreted into the blood and serves as the major binding protein for leptin in humans (24, 25, 26). It has been suggested that sOB-R may serve to transport leptin across the blood-brain barrier (27) or across the placental barrier during pregnancy (28). It may also function to reduce the clearance of leptin, prolonging its half-life in the circulation (29). For example, induced overexpression of the sOB-R in the leptin-deficient mouse increases the effectiveness of exogenously administered leptin in reducing food consumption and body weight (29). On the other hand, under physiological conditions (e.g. lean human subjects with leptin predominantly in the bound form) the increased binding of leptin in the circulation to the sOB-R may reduce the amount of free leptin available to bind to receptors that are involved in cellular signaling, as the affinities of the two receptors for leptin are comparable (30). In a preliminary study from our laboratory (31) we reported that circulating leptin and leptin receptor levels were inversely related in both boys and girls during development. Others (25) have shown that circulating leptin-binding activity decreased with age and pubertal development in children. As a result, in developing children bioavailable leptin may be increasing more rapidly than is indicated by changes in total leptin concentrations. These changes in bioavailable leptin could alter the tempo of pubertal development.

To more fully characterize the relationship between leptin and human pubertal development, we examined changes in circulating concentrations of leptin, the sOB-R, and gonadal hormones from birth until the onset of puberty in 192 children (92 boys and 100 girls). We also measured serum leptin and leptin receptor levels in healthy male (n = 45) and female (n = 30) adults between the ages of 21–93 yr.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study protocol

The study protocol was approved by the institutional review board of Texas Tech University School of Medicine (Amarillo, TX). There were three components to this study. In the first, blood samples drawn (1000–1600 h) from normal boys (n = 92) and girls (n = 100) ranging from 0–20 yr of age were assayed for leptin, sOB-R, estradiol (females only), and testosterone (males only). In a smaller subgroup of these subjects in whom body mass indexes (BMIs) were available, we correlated BMI with circulating leptin and sOB-R levels. The ages of these subjects ranged from 0–30 yr, the breakdown being: 0–6 yr, n = 12; 7–12 yr, n = 18; and 13–30 yr, n = 30. Males and females were evenly distributed across these age ranges, and there were 32 boys and 27 girls. The mean BMI (±SEM) for males in this subgroup was 22.4 ± 2.2; for females it was 26.5 ± 2.1 kg/m2. We also measured circulating concentrations of leptin, sOB-R, estradiol (females only), and testosterone (males only) in normal adult male (n = 45) and female (n = 30) subjects, 21–93 yr of age. The study population consisted largely of Caucasians (60%) and Hispanics (20%). Blacks and Orientals made up the remaining 20%.

Assays

Serum samples were assayed for leptin (immunoradiometric assay, Diagnostic Systems Laboratories, Inc., Webster, TX), sOB-R (ELISA, Bio Vender Laboratory Medicine, Inc., Brno, Czech Republic), estradiol (females only; chemiluminescent assay, Immulite, Diagnostics Products, Los Angeles, CA), and testosterone (males only; chemiluminescent assay, Immulite, Diagnostic Products). It should be noted that the leptin receptor assay was not affected by the addition of as much as 200 ng/ml human leptin (4-fold greater than the normal clinical range of leptin values) to the standards, unknowns, or controls. Minimum detection limits for leptin, sOB-R, estradiol, and testosterone assays were, respectively, 0.25 ng/ml, 2 U/ml (4 ng/ml), 15 pg/ml, and 10 ng/dl. The interassay coefficients of variation for the four assays were, respectively, 9.2%, 5.4%, 6.2%, and 12.9%. Intraassay coefficients of variation were less than 5% for all assays. According to the manufacturer of the sOB-R assay, 1.0 U was equivalent to 2 ng receptor.

Statistics

Development data were initially divided into four major groups (males, females, age 0–20, and age 21–92 yr) and then analyzed by ANOVA, followed when appropriate (when a significant overall effect of age was observed) by the least significant difference test for multiple comparisons across age groups (SPSS, Advanced Statistics 6.1, SPSS, Inc., Chicago, IL). The relationships among age, serum leptin, sOB-R, testosterone, and estradiol levels were assessed in boys and girls by the Pearson correlation test. Relationships between variables were modeled using linear and curvilinear methods. Nonlinear models were applied to reflect both biological and statistical relationships between the variables of particular interest (e.g. age, leptin, and sOB-R). We also correlated BMI and serum leptin and leptin receptor levels during development in the subgroup of subjects in whom BMI values were available using this same test. Data were considered significant at P <= 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Age-related changes in male subjects

Illustrated in Fig. 1Go are age-related changes in serum leptin (upper panel), sOB-R (upper panel), and testosterone (lower panel) in males. In young male subjects (<21 yr of age) data are combined in age groups of 3–4 yr, and in older subjects (age, >21 yr) data are combined in age groups of 10–20 yr. In the younger group circulating concentrations of leptin and testosterone increased (P = 0.037 and P = 0.0001, respectively) with age in association with declining levels of sOB-R (P < 0.0001). A significant rise in leptin and decrease in the sOB-R (relative to values for the 0–3 and 4–6 yr age groups) occurred at a younger age (10–12 and 7–9 yr, respectively) than the pubertal rise in testosterone (13–15 yr of age). In these young males, serum leptin (Fig. 2Go, upper panel) and testosterone were positively correlated with age (r = 0.619; P < 0.0001; data not shown), and sOB-R concentrations were negatively correlated with age (Fig. 2Go, lower panel). Serum testosterone concentrations also showed a weak negative correlation with sOB-R levels (r = -0.228; P = 0.038) in these subjects (data not shown).



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  		FIG. 1. Mean serum leptin (±SEM) and sOB-R (upper panel) and testosterone (lower panel) concentrations in male subjects from birth until advanced age: 0–3 yr, n = 11; 4–6 yr, n = 10; 7–9 yr, n = 22; 10–12 yr, n = 20; 13–15 yr, n = 22; 16–20 yr, n = 7; 21–30 yr, n = 9; 31–40 yr, n = 7; 41–50 yr, n = 9; 51–70 yr, n = 9; and 71–90 yr, n = 11. *, Significantly different from the corresponding 0–3 yr age group.

 


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  		FIG. 2. Correlation of age with serum leptin (upper panel) and sOB-R (lower panel) concentrations in boys 20 yr of age or younger. Age and serum leptin concentrations in the upper panel were modeled using a fourth order polynomial regression method; age and sOB-R levels in the lower panel were modeled using a third order polynomial method.

 
In male subjects (0–30 yr of age), serum leptin and sOB-R concentrations showed a positive and a negative correlation (P < 0.0001 for both), respectively, with BMI (Fig. 3Go), and BMI increased significantly (P = 0.001) with increasing age (data not shown).



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  		FIG. 3. Relationship between serum leptin (upper panel) and sOB-R (lower panel) concentrations and BMI in a subgroup of males 30 yr of age or younger: 0–6 yr, n = 6; 7–12 yr, n = 9; and 13–30 yr, n = 18.

 
Serum leptin and sOB-R levels showed a strong negative correlation in young male subjects (<21 yr of age; Fig. 4Go, upper panel), but the magnitude of this correlation varied with the leptin concentration. At leptin concentrations below 10 ng/ml, the range of sOB-R values was considerably greater than those related to leptin concentrations above 10 ng/ml.



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  		FIG. 4. Correlation between serum levels of sOB-R and leptin concentrations in boys (upper panel) and girls (lower panel) 20 yr of age or younger. Data in the upper and lower panels were modeled using an exponential method.

 
In males older than 20 yr of age (Fig. 1Go), there was no significant effect of age on serum leptin, sOB-R, or testosterone concentrations, although the effect of age on sOB-R concentrations almost reached levels of significance (P = 0.059). The trend was for levels of sOB-R to be higher in male subjects older than 30 yr of age compared with subjects 21–30 yr of age. In general, subjects older than 20 yr of age had higher sOB-R and lower leptin concentrations than adolescent subjects (10–20 yr old; Fig. 1Go, upper panel). In contrast to younger male subjects, serum leptin and sOB-R were not significantly correlated in older male subjects.

Age-related changes in female subjects

In female subjects less than 21 yr of age, serum leptin, sOB-R, and estradiol concentrations all changed significantly with age (P < 0.0001 for all three parameters; Fig. 5Go). The age-related pattern in these young female subjects was similar to that observed in males (Fig. 1Go), i.e. an increase in leptin and gonadal hormone (estradiol) concentrations (Fig. 5Go, upper and lower panels) and a decrease in sOB-R with age (Fig. 5Go, upper panel). As in boys, the rise in leptin and the decline in sOB-R in girls occurred at a younger age (10–12 and 4–6 yr of age, respectively, compared with the two younger age groups) than the pubertal rise in estradiol (16–20 yr of age; Fig. 5Go).



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  		FIG. 5. Mean serum leptin (±SEM) and sOB-R (upper panel) and estradiol (lower panel) concentrations in female subjects from birth until advanced age: 0–3 yr, n = 16; 4–6 yr, n = 17; 7–9 yr, n = 17; 10–12 yr, n = 20; 13–15 yr, n = 14; 16–20 yr, n = 16; 21–50 yr, n = 13; and 51–93 yr, n = 17. *, Significantly different from the corresponding 0–3 yr age group.

 
Throughout sexual development, serum leptin and sOB-R levels were positively and negatively correlated, respectively, with age in young female subjects (Fig. 6Go). There was also a positive and a negative correlation, respectively, of serum leptin and sOB-R concentrations with BMI in female subjects (0–30 yr of age; Fig. 7Go).



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  		FIG. 6. Correlation of age with serum leptin (upper panel) and sOB-R (lower panel) concentrations in girls 20 yr of age or younger. Age and serum leptin concentrations were modeled in the upper panel using an exponential method; age and sOB-R levels in the lower panel were modeled with a third order polynomial method.

 


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  		FIG. 7. Relationship between serum leptin (upper panel) and sOB-R (lower panel) concentrations and BMI in a subgroup of females 30 yr of age or younger: 0–6 yr, n = 6; 7–12 yr, n = 9; and 13–30 yr, n = 12.

 
The lower panel of Fig. 4Go illustrates the relationship between serum leptin and sOB-R concentrations in young female subjects. These two parameters were negatively correlated with each other, and, as in boys, the serum leptin concentration was a poorer predictor of sOB-R values at lower concentrations (<10 ng/ml) than at higher concentrations (>10 ng/ml) of the hormone.

In women older than 20 yr of age, there was no effect of age on serum leptin, sOB-R, or estradiol concentrations (Fig. 5Go). Serum leptin and sOB-R levels in these older female subjects were comparable to values in adolescent girls. Interestingly, and in contrast to older male subjects, serum leptin and sOB-R concentrations exhibited a highly significant negative relationship (r = -0.610; P < 0.0001, data not shown) in older female subjects.

Gender-dependent and age-dependent gender-specific differences in leptin and the sOB-R

There were gender-specific and age-dependent gender-specific differences in leptin and sOB-R levels. In older (>20 yr of age), but not younger, subjects, serum leptin levels were higher (P < 0.0001) in females (36.6 ± 4.6 ng/ml) than in males (14.4 ± 1.5 ng/ml). Conversely, serum sOB-R concentrations were higher (P < 0.0001) in both age groups of male subjects compared with age-matched female subjects (young subjects: males, 40.8 ± 2.5 U/ml; females, 26.8 ± 1.7 U/ml; older subjects: males, 52.7 ± 3.9 U/ml; females, 19.4 ± 2.0 U/ml).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the current study serum leptin levels increased with age during childhood and adolescence as levels of the sOB-R declined in both sexes. Most significantly, these developmental changes, which compositely represent an increase in circulating bioavailable leptin, preceded the pubertal rise in serum testosterone in boys and estradiol in girls. Thus, these changes in leptin might potentially serve as a metabolic barometer that informs the central nervous system that energy reserves are adequate to support pubertal development. The data from this study further suggest that leptin is a major regulator of its own binding protein (i.e. sOB-R) in the circulation, but importantly, the magnitude of the hormone’s role in this process may depend on its concentration. Serum leptin and the sOB-R concentrations exhibited a strong negative correlation throughout development, but leptin concentrations were less reliable as a predictor of sOB-R levels when an individual’s leptin level was relatively low (<10 ng/ml). The data suggest that leptin may play a more prominent role in this process during situations when circulating leptin concentrations are elevated (e.g. obesity).

We also found that there are gender-specific and age-dependent gender-specific differences in serum leptin and sOB-R concentrations during development. Although the developmental pattern of serum leptin and sOB-R did not differ substantially in boys and girls through the onset of puberty, mean levels of serum sOB-R in young male subjects (<21 yr of age) were significantly higher than those in young female subjects. In contrast, we did not detect any significant gender differences in leptin in these young subjects. In older subjects the gender differences in serum sOB-R not only were retained, but were also increased in magnitude in association with now very prominent gender-specific differences in serum leptin concentrations. There were no significant age-related changes in sOB-R in older subjects. To the best of our knowledge, this sexual dimorphism in circulating sOB-R concentrations during development has not been reported previously.

Although a role for leptin in pubertal development in primates has been suggested, most of this speculation has been based largely on circumstantial evidence. There appears to be little, if any, direct evidence that an increase in leptin is the timing trigger for puberty in primates, although there are considerable clinical data (and rodent data as well) that support the concept that leptin plays a permissive role in this process (see reviews in Refs.6, 7, 8). A number of studies, both longitudinal and cross-sectional, have examined developmental changes in circulating leptin in children. The majority of these studies (19, 20, 32, 33, 34) have found that there is a developmental increase in leptin during childhood and early adolescence that precedes the initiation of major pubertal events. One of these studies reported that a transient elevation of leptin occurred before the initiation of the pubertal rise in testosterone secretion in boys (20). The data from the current study confirms previous reports that showed a developmental increase in circulating leptin in both boys and girls that preceded the pubertal rise in gonadal hormones. Our data extend these findings, in that while serum leptin levels are increasing in children, there is a concurrent decline in serum sOB-R concentrations. Thus, bioavailable leptin appears to be increasing during development at a faster pace than indicated by changes in total leptin concentrations. The data are also consistent with a report that leptin-binding activity in the circulation decreases with age in children (25).

While the current report was being prepared, another study was published that examined developmental changes in circulating leptin and the sOB-R in children (34). The data reported here agree largely with those from that study, with some notable exceptions. Both studies found that there is a developmental increase in leptin and a reciprocal decline in sOB-R levels in both boys and girls. Although the former report indicated that there were no gender differences in the pattern of these changes, and we concur with these findings, we also documented that there were gender-specific differences in the mean levels of the sOB-R that were not reported by the other group. As a result, although mean serum leptin values did not differ between male and female subjects younger than 21 yr of age, mean sOB-R concentrations were significantly higher in males than in females. Thus, although leptin may play an important role in the regulation of circulating levels of the sOB-R, as alluded to earlier, at least in young children and adolescents there also appears to be a leptin-independent mechanism involved in regulating the circulating concentrations of this binding protein.

The present study also extends the former study (34) in that we also examined the effect of age on circulating levels of sOB-R from puberty to advanced age (90+ yr) in men and woman. As reported by others (35, 36), serum leptin concentrations were higher in women than in men (>2-fold), but serum leptin concentrations did not change with age in either sex. Mean levels of the sOB-R in adult male subjects remained (as in young subjects) higher than values in women (nearly a 3-fold difference). This resulted from the fact that sOB-R levels rose between adolescence (13–20 yr of age) and early adulthood (31–40 yr of age) in male subjects and remained elevated in later years as well. In contrast, serum sOB-R concentrations remained low in older women and did not differ from those in adolescent girls. These data are in agreement with data from earlier studies showing that proportionally more leptin is bound in the circulation in men (less in the free state) than in women and may explain the greater leptin resistance in women vs. men (30, 37, 38).

Because assays for the sOB-R in the circulation were not available until recently, relatively few studies on the binding protein have been published to date. With the exception of the Kratzsch study (34), published data have been confined to adult subjects (27, 39). In one study there were gender differences in serum sOB-R levels in adults grouped by BMI, and levels were higher in underweight than normal weight subjects (27). As we report here for young subjects, sOB-R levels were inversely related to serum leptin concentrations (27, 39). In women, serum sOB-R concentrations did not change significantly during the menstrual cycle (27). Perhaps this explains why we were unable to show any difference in serum sOB-R levels between women in their reproductive years (20–50 yr old) and those who were probably menopausal (>50 yr old).

The relationship between sOB-R levels in the circulation and obesity may help to explain the relative leptin resistance of the morbidly obese patient. Overweight and obese individuals have higher serum leptin levels and lower serum sOB-R values, and more leptin circulates in the bioactive free form (38). The higher free leptin levels do not lead to a decline in caloric intake or increased energy expenditure, suggesting leptin resistance (40). Weight loss is associated with a reduction of leptin levels, a rise in serum levels of sOB-R, and a reduction in circulating free leptin concentrations (38, 41), emphasizing the dynamics of the relationship between circulating leptin and sOB-R. Fasting lean men for 72 h resulted in a decline in serum leptin and an increase in serum sOB-R levels (38). Importantly, the administration of recombinant human leptin abolished the fasting-induced increase in sOB-R concentrations. These data suggest the importance of leptin in the regulation of its major binding protein in the circulation.

It appears likely that most of the circulating sOB-R is derived from proteolytic cleavage of membrane-bound receptor (27, 41). It might be proposed that when leptin levels increase above a certain threshold, a decrease in proteolytic cleavage of membrane-associated receptor would result in a decline in serum sOB-R levels, a decrease in the proportion of leptin bound in the circulation, and an increase in free leptin. This mechanism may only be functional when leptin values are above a certain threshold. Perhaps this helps to explain why in the current study there was less of a correlation (negative) between serum leptin and sOB-R when leptin concentrations were 10 ng/ml or less in children and adolescents. It may also help to address the issue why sOB-R concentrations were nearly 3-fold higher in men than women in the present study. One would expect that this mechanism would be less functional in men, in whom serum leptin concentrations were relatively low compared with those in women. In support of this theory, serum leptin and sOB-R concentrations were significantly correlated (negatively) in women, but not men, in the present study. It is likely, however, that additional unidentified factors are involved in the regulation of the sOB-R, because we were able to document gender-specific differences in sOB-R levels in children and adolescents despite the lack of gender differences in serum leptin.


   Acknowledgments
 
We are indebted to Mr. Scott A. Bishop, M.S. (Biostatistician/Epidemiologist, Diagnostic Systems Laboratories, Inc.), for his expert help modeling variables using linear and curvilinear methods.


   Footnotes
 
This work was supported by NIH Grants HD-41749 and GM-08248 (to Morehouse School of Medicine).

Present address for V.D.C.: Diagnostic Systems Laboratories, Inc., Webster, Texas.

Abbreviations: BMI, Body mass index; sOB-R, soluble leptin receptor.

Received December 26, 2002.

Accepted March 16, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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