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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3659-3664
Copyright © 2005 by The Endocrine Society

A Twin Study for Serum Leptin, Soluble Leptin Receptor, and Free Insulin-Like Growth Factor-I in Pubertal Females

Hong-juan Li, Cheng-ye Ji, Wei Wang and Yong-hua Hu

Institute of Child and Adolescent Health (H.-j.L., C.-y.J., W.W.), Peking University Health Science Center, Beijing 100083, China; and Department of Epidemiology and Statistics (Y.-h.H.), School of Public Health, Peking University, Beijing 100083, China

Address all correspondence and requests for reprints to: Dr. Cheng-ye Ji, Institute of Child and Adolescent Health, Peking University Health Science Center, No. 38, Xueyuan Road, Haidian District, Beijing 100083, China. E-mail: jichengye{at}263.net.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Leptin and IGF-I are two peripheral metabolic signals linking body energy status to hypothalamus GnRH generator and involved in the pubertal development and metabolic disorders. The changes of their biological activity through puberty and the genetic basis are not clear.

Objective: To determine the genetic and environmental influences to the variations of basal leptin, soluble leptin receptor (SOB-R), free leptin index (FLI), and free IGF-I levels in pubertal females.

Design: A twin study was performed in 2003.

Setting: Participants were recruited from the Qingdao Twin Registry, a school-based registry.

Participants: A total of 360 twin girls aged 6–18 yr were enrolled, consisting of 132 pairs of monozygotic and 48 pairs of dizygotic twins.

Interventions: Anthropometric and sexual characteristics were examined. Serum total leptin and free IGF-I were measured by immunoradiometric assay, and SOB-R was measured by ELISA.

Main Outcome Measure: Estimates of genetic and environmental components of variance were based on the theory of normal maximum likelihood in Mx package, a computer program specifically designed for the analysis of twin and family data.

Results: Serum leptin concentrations increased persistently throughout puberty, especially from Tanner stage III to Tanner stage IV (P < 0.05), which in consistent with the increase of percentage of body fat. However, SOB-R decreased significantly from Tanner stage I to Tanner stage II (P < 0.05), which results in a continuous rise of FLI (ratio of leptin to SOB-R), especially from Tanner stage I to Tanner stage II (P < 0.05). Serum free IGF-I increased dramatically from Tanner stage I to II and declined since then. Results of correlation analysis suggest that FLI predicts the pubertal growth and sexual maturation more effectively, whereas leptin sensitively reflects the fat mass of body composition. Quantitative genetic model fittings showed that SOB-R and free IGF-I have higher heritability (0.62–0.77, 0.54–0.66) and leptin and FLI have lower heritability (0.38–0.48, 0.44–0.55).

Conclusions: Fast increase of FLI and free IGF-I from Tanner stage I to II might be involved in the onset of puberty and the onset of thelarche. The peak of free IGF-I in Tanner stage II might be presumed as an indicator of the peak of pubertal growth spurt in females, and the significant rise of leptin along with percentage of body fat from Tanner stage III to IV might be as a predictor of the forthcoming menarche. Our results stress the importance of research into the genetic regulation on the endocrine regulators involved in the pubertal development and metabolic disorders, including pubertal obesity and diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GENETIC AND ENVIRONMENTAL effects on pubertal development are most likely to be mediated through their influences on pubertal regulators. It has been well known that the energy regulating system plays a pivotal role in the pubertal development of females. The "Somatometer" hypothesis proposed that factors that regulate or emanate from the rapid increments in body composition at the transition to puberty might be important in regulating the onset of puberty (1). Two such growth-derived signals, leptin and IGF-I, are leading candidates linking peripheral energy status to hypothalamus to regulate the developmental increase of GnRH secretion (2, 3, 4, 5, 6, 7). This hypothesis is supported by Suter et al. (8), who first demonstrated that nocturnal leptin and GH-induced IGF-I secretion increase before the onset of puberty in primates and that these developmental changes occur independently of the gonadal influences (8).

However, the biological activities of leptin and IGF-I are regulated by the binding proteins of circulation and the receptor levels of the target tissues (9, 10, 11). Only free forms of leptin and IGF-I could be transported into the hypothalamus through the blood-brain barrier and act as central regulators. Free IGF-I, the active form of circulating IGF-I (12), is relatively stable under regulation of the IGF binding proteins and ensures the normal postnatal growth and development (13). Leptin also exists in a free form and in a form bound to carrier protein in the serum (14). It has been proven that soluble leptin receptor (SOB-R) is the major leptin binding protein in human circulation and determines the biological activity of leptin (15). Free leptin index (FLI), the ratio of leptin to SOB-R, being presumed as an index representing the active form of leptin (16), has been demonstrated to be related more closely to the parameters of growth and sexual maturation than leptin alone (17). SOB-R is also a potential modulating factor of leptin sensitivity (18), and free IGF-I is related to the physiological insulin resistance in puberty (9, 19). Both leptin resistance and insulin resistance are important mechanisms of many pubertal metabolic disorders, such as obesity and diabetes. Therefore, SOB-R, FLI, and free IGF-I play important roles in regulating pubertal development and metabolic disorders. Determinations of FLI and free IGF-I are additional valuable tools to investigate the roles of leptin axis and somatotropic axis during growth and sexual maturation.

A few studies have shown moderate genetic effects on the serum leptin and IGF-I concentrations (20, 21). But relatively few studies have paid attention to the changes and individual differences of SOB-R, FLI, and free IGF-I levels during puberty and the etiology of these differences, in particular their possible genetic basis. The objective of this study is to determine the genetic and environmental influences to the variations of basal leptin, SOB-R, FLI, and free IGF-I levels in the pubertal girls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Participants were 132 monozygotic (MZ) and 48 dizygotic (DZ) female twin pairs (n = 360 individuals) aged 6–18 yr from the younger cohort of the Qingdao Twin Registry, a school-based twin registry, which consists of 2045 pairs of twins aged 6–18 yr. The participants of this study were prescreened by phone, and all of them were free of metabolic diseases and raised together with their cotwins in the same families. Written informed consents were obtained from all participants and from the parents of those under 18 yr old. The design of this study was approved by the Board of Medical Research and Human Ethics Committee of the Peking University Health Science Center.

Zygosity diagnosis

Zygosity of the 180 pairs of twins was determined by DNA fingerprinting. The AmpF1 STRProfiler Kit (PE Applied Biosystems, Foster City, CA), which coamplifies the repeat regions of nine short tandem repeat loci (D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820) and a segment of the X-Y homologous gene amelogenin, was used.

Anthropometric measurement and sex characteristics examination

Anthropometric measurements were performed according to a standardized technique (22). Body height was measured to the nearest 0.1 cm with a fixed standiometer. Body weight was determined to the nearest 0.1 kg. Body mass index (BMI) was calculated as [weight (kilograms)]/[height (meters)]2. Waist and hip circumferences were measured to the nearest 0.1 cm, at the level of umbilicus and the maximum extension of the buttocks, respectively. Waist to hip circumference ratio (WHR) was calculated as [waist circumference (centimeters)]/[hip circumference (centimeters)] x 100. Right-handed skinfold thicknesses were measured to the nearest 1 mm at the standardized sites of the mid triceps, and subscapular with a keys caliper. The body density and the percentage of body fat (BF%) were calculated by the Changling-Brozek equations (22), which were specially suitable for the Chinese youth. Breast development was examined according to the Tanner standard (23) and taken for the symbol of pubertal stage (from Tanner stage I to V), and the age of thelarche (appearance of breast buds), menarche, and latest menstrual date were recorded.

Blood sampling and endocrine factors measurements

After an overnight (12-h) fasting state, blood samples were taken between 0800 and 0900 h from the cubital vein, and the same-pair twin’s blood was taken at the same time. For those girls who had begun menarche, blood samples were taken in the preovulatory phase (d 10–12; d 1 is the first day of menstrual bleeding) to avoid the effect of LH peak in the luteal phase on leptin secretion (24). Blood clot and serum were separated by centrifuging and frozen at –40 C until the measurements were performed. Blood clots were used to extract DNA and diagnose zygosity. Serum total leptin and free IGF-I were measured by immunoradiometric assay, and SOB-R was measured by ELISA. All kits were bought from Diagnostic Systems Laboratories, Inc. (Webster, TX). Sensitivity was 0.10 ng/ml for leptin, 0.2 ng/ml for SOB-R, and 0.03 ng/ml for free IGF-I, respectively. Standard curves were fitted for leptin and free IGF-I by five-parameter model and for SOB-R by bilogarithms linear model in Origin software package (Microcal Software Inc., Northampton, MA). All the goodness-of-fit (R2) were greater than 0.999. The intraassay variations for all kits in both high and low level controls were less than 5%. All the measurements were finished within 6 months. FLI was calculated with the formula FLI (%) = [leptin (nanograms per milliliter)/SOB-R (nanograms per milliliter)] x 100.

Statistical analysis

Normality was assessed for all continuous variables and transformed the nonnormality distributed variables into natural logarithms when performing the statistical tests and model fitting. General statistical analyses were done by SPSS 10.0 (SPSS, Inc., Chicago, IL). All quantitative genetic model-fitting was done with Mx, a computer program specifically designed for the analysis of twin and family data. The model-fitting was based on raw data by the normal theory maximum likelihood (25, 26, 27). Our models specified additive genetic effects (A), shared environmental effects (C), individual or unique environmental effects (E), and age regression. E also contains measurement error. The total phenotypic variation equals A + C + E + age. Division of each of these components by the total variance gives the different standardized components of variance, for example the heritability (h2), which can be defined as the proportion of overall phenotypic variation that can be explained by additive genetic factors. The significance of variance of components A, C, E, and age was assessed by removing each sequentially in submodels and testing the deterioration in model fit after each component was dropped from the full model. This eventually leads to a model in which the pattern of variances and covariance is explained by as few variables as possible. Overall goodness-of-fit was assessed with {chi}2 and Akaike’s information criterion (Akaike’s information criterion = {chi}2 – 2df). The submodel with the lowest Akaike’s information criterion is the best fitting. Estimates of the quantitative genetic variable and 95% confidence intervals were obtained from the best-fitting model. The following formulas and path diagram (Fig. 1Go) were used:



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  		FIG. 1. Path diagram of model-fitting for twin data. Observed variables are shown in squares and latent variables (or factors) are shown in circles. A single-headed arrow indicates a direct influence of one variable on another, its value represented by a path coefficient. Double-headed arrows between two variables indicate a correlation without any assumed direct relationship. h, Additive genetic factor loading; c, shared or common environmental factor loading; e, unique environmental factor loading; v, factor loading on age; sd, SD of age; rg, genetic correlation (1 for MZ and 0.5 for DZ twins); rc, shared environmental correlation (1 for both MZ and DZ twins).

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
General characteristics and serum hormones of female twins

Table 1Go lists the general characteristics and serum hormone concentrations for MZ and DZ female twin pairs. All data were reported as mean ± SE. No significant difference is found between MZ and DZ in all indices. Therefore, MZ and DZ were combined for ANOVA and correlation analyses; the results are shown in Tables 2Go and 3Go.


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  		TABLE 1. General characteristics and serum endocrine factors in MZ and DZ female twins (mean ± SE)

 

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  		TABLE 2. Changes of general characteristics and endocrine factors from Tanner stage I to V in total female twins (mean ± SE)

 

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  		TABLE 3. Correlating coefficients of endocrine factors and general indices in total female twins

 
Table 2Go presents the BMI, BF%, and the serum free IGF-I, leptin, SOB-R concentrations, and FLI from Tanner stage I to Tanner stage V in total female twins. BF% and BMI increase throughout puberty. The increase of BF% is significant from Tanner stage III through Tanner stage V (P < 0.05). Serum free IGF-I concentrations increase from Tanner stage I to II (P < 0.05) and decline later. Serum leptin concentrations increase persistently throughout puberty, especially from Tanner stage III to IV (P < 0.05), whereas SOB-R significantly declines from Tanner stage I to II (P < 0.05), which results in a sustained increase of FLI throughout puberty, especially from Tanner stage I to II (P < 0.05).

Results of Pearson correlation analysis for the serum endocrine factors and anthropometric indices are presented in Table 3Go. All factors but SOB-R are positively correlated with age and pubertal stage. The correlations for the FLI with age, Tanner stage, and growth parameters such as height and body weight are greater than that of the leptin. However, leptin correlates more closely with body fat mass and BMI than FLI. The correlations of leptin and FLI with Tanner stage are greater than that with age. SOB-R shows negative correlation with age, Tanner stage, and all growth parameters shown above except WHR.

Intrapair similarity, difference, and heritability analysis of endocrine factors in pubertal female twins

Table 4Go presents the average intrapair differences, coefficients of similarity, and intraclass correlations of the MZ and DZ female twins. A higher intraclass correlation but lower coefficient of similarity and average intrapair difference of the MZ than DZ are seen for all the factors, which means that MZ has higher intrapair resemblance and lower intrapair difference than DZ in these endocrine factors in pubertal females.


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  		TABLE 4. Estimates and 95% confidence interval of average intra-difference, coefficient of similarity, and intraclass correlation in MZ and DZ female twins

 
Results of heritability estimating for leptin, SOB-R, FLI, and free IGF-I are presented in Table 5Go. We analyzed the data with quantitative model-fitting to estimate the genetic and environmental variance components. The additive genetic components explain the substantial proportions of the total variance, ranging from 42% for leptin to 69% for SOB-R. Other variance components can be explained by the unique environmental factor and age. The effects of age on leptin, FLI, and free IGF-I were significant and explain from 18% for free IGF-I to 26% for FLI of the total variance as modeled in the linear regression. No significant common environmental component was recorded for any of the factors.


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  		TABLE 5. Estimates and 95% confidence interval of genetic and environmental variance on endocrine factors in pubertal females

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The preponderance of previous studies have focused on how leptin and IGF-I serve as metabolic signals of energy balance within the neuroendocrine system, particularly as regulators of GnRH secretion (28, 29, 30, 31). But as peripheral regulators, less research has been conducted with metabolic or biological activity of circulating leptin and IGF-I and the genetic basis in vivo.

In this study, we described the changes of serum leptin, SOB-R, FLI, and free IGF-I levels throughout puberty in a large number of female twins and quantified the genetic and environmental effects on these peripheral regulators in female puberty with twin design. Considerable heritabilities were reported for most of the factors, and the larger heritabilities were estimated for SOB-R and free IGF-I. Age had a significant effect on all the factors except for the SOB-R, with concentrations increasing with age.

Our study demonstrates a growth-related increase for serum leptin throughout female puberty, consistent with the increase of the BF%, whereas a decline for SOB-R from Tanner stage I to Tanner stage II results in a sustained increase for FLI. Serum free IGF-I increased dramatically from Tanner stage I to II and declined later. Fast increase of FLI and free IGF-I from Tanner stage I to Tanner stage II might be involved in the onset of puberty and the thelarche. This result is consistent with the previous view that the GH-IGF-I system underlies the earlier breast development (32). Free IGF-I peak in Tanner stage II might be presumed as an indicator of the peak of pubertal growth spurt in females, and the significant rise of leptin along with the BF% in the latter stages of puberty might be a predictor of the forthcoming menarche. Results of correlation analysis suggest that FLI predicts the pubertal growth and sexual maturation more effectively, whereas leptin sensitively reflects the fat mass of body composition. SOB-R is less influenced by body composition. In females, the BF% was the best predictor of serum leptin. Studies in humans demonstrate a positive correlation between the release and synthesis of leptin and BMI or BF% (33). Our study showed that serum leptin levels are strongly correlated with BMI or fat mass and increase continuously throughout puberty, consistent with a number of previous studies (34, 35, 36). Heritabilities estimated also support this deduction: leptin is fairly influenced by the environmental factors, whereas SOB-R is substantially controlled by the genetic factors (h2 = 0.69).

Our heritability estimated for leptin (0.38–0.48) is less than in the previous study by Narkiewicz et al. (20) in females at an average age of 20 yr (0.73), which might be attributed to the difference of age. Our subjects (average age, 11.75 yr) are in the process of pubertal development and are much more prone to be affected by outside diversification, especially the nutrition intake; body composition tends to be more sensitive to the nutrition status. Hence, even within a pair of twins more differences are demonstrated. Leptin is produced by adipose tissue, and it sensitively reflects the fat mass of body composition and is consistent with the change of fat mass.

The study of Kratzsch et al. (17) for 581 healthy children and adolescents demonstrates significant inverse relationships of SOB-R with age, IGF-I levels, pubertal stages, auxological and body composition parameters, as well as leptin concentrations. Correlation analyses demonstrate that in particular parameter of growth and sexual maturation are more closely related to the FLI than to leptin alone (17). Mann et al. (37) also demonstrate that the increasing extent of free leptin, a biologically active form, is more significant than total leptin during pubertal development. Our study also demonstrates a sustained rise of FLI throughout puberty in females. That the correlations of leptin and FLI with Tanner stage were greater than with chronological age indicates that maturational stage is a better predictor of the serum leptin and FLI.

Free IGF-I is the active form and accounts for 1% of the total IGF-I (38). A central growth-tracking device that is sensitive to circulating peripheral growth-related cues might react to free IGF-I and underlie the increase in GnRH release at puberty (39, 40, 41). Our study results in a conclusion that the serum free IGF-I in pubertal females is substantially determined by the genetic factors (h2 = 0.54–0.66). The study of Verhaeghe et al. (21) for 110 pairs of umbilicus blood twins demonstrated that IGF-I was mainly controlled by genetic factors, and the heritabilities are 0.77 and 0.93 for girls and boys, respectively. Additional research is necessary to determine whether the IGF-I system is predominantly controlled by the genetic factors during the fetal and pubertal growth-spurt periods in females.

Physiological pubertal insulin resistance is associated with the rise of IGF-I secretion for activation of GH-IGF-I axis. Leptin resistance is related to serum SOB-R concentration. Both insulin resistance and leptin resistance are physiological foundations of many metabolic disorders. Accordingly, genetic factors might play an important role in the mechanism of these pubertal metabolic disorders.

This study explores the influence of genetic and environmental factors on several metabolic regulators in the pubertal development of females. The moderate to large degree of heritabilities in peripheral growth-derived regulators that we have reported indicates the importance of research into the genetic regulation of factors involved in the pubertal development and metabolic disorders, including pubertal obesity and diabetes.


   Acknowledgments
 
We thank Z. C. Peng, S. J. Wang, and other members of the Qingdao Twin Association for providing access to the twin registry, and especially all our twin volunteers for their support. We deeply appreciate the technical assistance of the Medical Jurisprudence Appraises Center, Beijing Public Security Bureau in diagnosing the twin zygosity. We are grateful to the anonymous reviewers for their invaluable comments, advice, and suggestions.


   Footnotes
 
This work was supported in part by the Chinese National Natural Science Fund (C030104-30371223) and in part by the 973 national grants, Ministry of Sciences and Technology, China (2001CB510310).

First Published Online March 22, 2005

Abbreviations: %BF, Body fat percentage; BMI, body mass index; DZ, dizygotic; FLI, free leptin index; MZ, monozygotic; SOB-R, soluble leptin receptor; WHR, waist to hip circumference ratio.

Received October 25, 2004.

Accepted March 14, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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