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Original Article |
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (J.K., A.L., B.S., J.T.), Hospital for Children and Adolescents (A.L., A.B., B.S., G.M., W.K.), University of Leipzig, 04103 Leipzig, Germany; and Department of Child and Adolescent Psychiatry of the University of Marburg (J.H.), 35039 Marburg, Germany
Address all correspondence and requests for reprints to: Dr. J. Kratzsch, Department of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Liebigstrasse 27a, D-04103 Leipzig, Germany. E-mail: Kraj{at}medizin.uni-leipzig.de.
Abstract
Leptin is bound in human blood by a high affinity binding protein, which appears to be identical with the soluble leptin receptor (sOB-R). Using a ligand-mediated immunofunctional assay for the determination of serum sOB-R, we investigated its course during childhood, puberty, and adolescence in a large cohort of 581 healthy children and adolescents and a small group of 13 patients with anorexia nervosa. In the first years of life, sOB-R is detectable in remarkably high concentrations. Thereafter, a continuous decline of sOB-R levels was found. Consequently, correlation analyses demonstrated significant inverse relationships (P < 0.001) of sOB-R with age, IGF-I levels, pubertal stage, auxological and body composition parameters, as well as with leptin concentrations. Multiple regression analysis revealed that height, IGF-I, and age (only in girls) were independent predictors of sOB-R levels; these variables account for approximately 65% and 48% of the variation of sOB-R levels in boys and girls, respectively. The courses of age-dependent median values for the free leptin index (FLI, ratio between leptin and sOB-R levels) and for leptin levels were parallel in both genders. Correlation analyses demonstrated that in particular parameters of growth and sexual maturation are more closely related to the FLI than to leptin alone; this closer relationship is more pronounced among boys. Weight gains of patients with anorexia nervosa resulted in a significant increase in leptin and IGF-I levels (P < 0.01), whereas the median of sOB-R values decreased (P < 0.01). sOB-R and IGF-I levels were again significantly correlated (r = -0.55, P < 0.01). These findings suggest that high levels of sOB-R in emaciation may reflect an up-regulation of the sOB-R to suppress leptin action during energy deficiency. Furthermore, determinations of sOB-R and FLI are additional valuable tools to investigate the leptin axis during growth and sexual maturation.
LEPTIN, A MEMBER OF the cytokine family, is mainly produced by adipocytes (1, 2). Biological effects of leptin in rodents include the suppression of food intake and the stimulation of energy expenditure and, consequently, the regulation of body weight (3, 4, 5, 6). Furthermore, leptin is involved in the control of the hypothalamic-pituitary-gonadal axis both in animals and in humans (7, 8, 9). Leptin-deficient or leptin-resistant subjects are hypogonadal (10, 11). Hence, leptin seems to be an important factor for initiation and progression of puberty (12, 13).
Human obesity is, however, associated with elevated leptin levels, suggesting central and peripheral leptin insensitivity (14, 15, 16). To understand the phenomenon, it is important to determine the interaction of leptin with other proteins in the circulation, which may alter its bioavailability and function.
Recently, we have shown that the soluble leptin receptor (sOB-R) is the major leptin binding protein in human circulation (17). The sOB-R occurs in two different N-glycosylated isoforms, which circulate as dimers and oligomers in human blood. Its physiological function in human circulation has not yet been fully elucidated, presumably partially due to the molecular diversity and to technical problems in the specific determination of sOB-R. The analytical methods used so far are based almost exclusively on the estimation of the amount of leptin bound to unknown proteins (18, 19, 20, 21, 22). To improve this, we have established a sensitive ligand-immunofunctional assay to measure specifically sOB-R. In analogy to the immunofunctional determination of GH-binding-protein (23), this method is able to measure exclusively molecules of the human sOB-R, which are capable of binding leptin.
We hypothesized that, during childhood and adolescence, leptin action and responsiveness may depend on gender, weight, and maturational status. Using this new in-house assay for the determination of sOB-R, we investigated its role during growth and pubertal development in a large cohort of healthy children and adolescents as well as in patients with anorexia nervosa during weight gain. The results show a leptin-independent decrease of the sOB-R levels throughout childhood and puberty until low adolescent levels are reached. Furthermore, age, height, and IGF-I appear to be the most important predictive parameters for the variation of serum sOB-R.
Materials and Methods
Subjects
Blood was obtained during routine investigations of pediatric patients with nonendocrine-related illnesses and from consecutively enrolled subjects of the Leipzig school children project, who were free of any acute and chronic disease (286 females and 295 males). Subjects were resting in supine position when blood was drawn from an anticubital vein between 0800 and 1100 h. Weight was measured to the nearest 0.1 kg on a calibrated balance-beam scale, and height was measured to the nearest 0.1 cm using the system of Dr. Keller (Günther GmbH, Tauscha, Germany). Skinfold measurements (subscapular, triceps, and biceps) were performed by the use of a skinfold caliper (Holtain Ltd., Crymmynch, UK). Distributions of age and body mass index (BMI) are shown in Table 1
. Stage of puberty was assessed according to Tanner. Written informed consent was obtained from the parents of each study subject and when ever possible from the children and adolescents themselves.
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Laboratory methods
The concentration of sOB-R was determined by a newly developed in-house ligand-immunofunctional assay. The wells of a microtiter plate were coated with anti-sOB-R IgG, raised in rabbits against recombinant sOB-R (R&D, Wiesbaden, Germany). Blocking of potentially unspecific binding sites was performed by incubation with PBS, 1% BSA for 1 h at room temperature. Ten microliters of rsOB-R standards ranging between 6.25 and 100 ng/ml or serum samples were added to the wells and incubated with an excess of biotinylated leptin in assay buffer (1% rabbit 
globulin, 0.1% BSA, and 0.05% Tween 20 in PBS) overnight at 4 C. For calibration, the recombinant sOB-R preparation of Liu et al. (25) was used. A standard curve of this rsOB-R demonstrated a parallel course with native sOB-R. The complex consisting of sOB-R and biotinylated leptin was detected by Europium-labeled streptavidin (Perkin-Elmer, Freiburg, Germany). Between coating, blocking, incubation, and detection steps the plate was washed three times with PBS, 0.05% Tween 20. The solid phase linked fluorescence signal of Europium was measured by the Victor-system (Perkin-Elmer). The resulting signal is thus dependent on both leptin binding and immunological recognition of the sOB-R. The lowest detectable sOB-R concentration in the assay was calculated to be less than 2 ng/ml. Intraassay and interassay coefficients of variation for two control samples were lower than 11.7% (n = 10). Results of dilution and sOB-R spiking experiments showed a recovery of 97.2 ± 11.8% and 92.4 ± 8.6% (n = 10), respectively, which is within the expected range for immunoassays. The assay was nearly insensitive to leptin interference. Increasing leptin levels up to 50 ng/ml led to a decrease of 6.4 ± 2.7% after linear regression analysis (n = 4), which is within the intraassay variation of the method.
Leptin was measured by an in-house RIA (26). Its intraassay and interassay coefficients of variation were lower than 12.5% in the range between 1 and 8 ng/ml leptin. The recovery of dilution experiments (undiluted to 1:20) was 88–112% for the concentration range between 4 and 6 ng/ml. Leptin levels of our in-house RIA (x) are comparable with data of a commercially available leptin RIA (y) from Mediagnost (Tuebingen, Germany) in sera of normal weight and obese subjects: y = - 0.13 + 0.96x (n = 92; r = 0.94, P < 0.0001).
Free leptin index (FLI) was determined by calculating the ratio between the levels of leptin and sOB-R, multiplied by 100.
The determinations of IGF-I and osteocalcin in serum were performed by immunochemilumimetric assays using the fully automated system Advantage from Nichols Institute Diagnostics (San Juan Capistrano, CA). The interference of IGF binding proteins is efficiently eliminated by the acidification of the sample and a subsequently added excess of IGF-II. Intra- and interassay coefficients of variation were less than 6.4% for both parameters.
Statistical analysis
Because some of the investigated parameters such as sOB-R, leptin, and IGF-I show a nonnormal distribution, nonparametric statistical methods (descriptive statistics by medians and quartiles, correlations according to Spearman U test) were applied for all analyses. Differences between protein levels among the age groups and in relationship to Tanner stage were evaluated by ANOVA according to Kruskal-Wallis. Comparisons between protein levels of individual age groups as well as Tanner stages were performed by the U test using the adjustment of Bonferoni. As log-transformation of sOB-R, leptin, and IGF-I values lead to normally distributed data in the subgroups of girls and boys, stepwise forward multiple regression analysis was performed gender dependently. All these results were calculated using the program Statistica 5.0 (Statsoft, Tulsa, OK). Confidence limits for the coefficients of correlation were estimated by the program Stat Xact-5, version 5.0.3 (Cytel Software Corp., Cambridge, MA).
Results
SOB-R levels of healthy children and adolescents
In the first years of life, remarkably high concentrations of sOB-R with a maximum approximately 2 yr after birth were detectable in both genders (Fig. 1). Thereafter, a continuous decline of sOB-R serum concentrations was found throughout late childhood and prepuberty. During puberty the sOB-R levels decreased significantly with increasing Tanner stages in both males and females (data not shown, P < 0.001). However, from Tanner stage III no further decrease of sOB-R was observable in both sexes. Hence, sOB-R concentrations seem to remain relatively constant during adolescence and early adulthood.
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). However, the correlation coefficient for the relationship between leptin and sOB-R was relatively low and the multiple regression analysis for both genders revealed that leptin was not an independent predictor of sOB-R. In boys, height (63%, P < 0.001) and IGF-I (1.9%, P < 0.001) were found to be independent inverse predictors of sOB-R levels and explain nearly 65% of its variation. The predicted variance in girls was 48% and therefore lower than in boys; age (42.9%, P < 0.001) and again IGF-I (5.1%, P < 0.001) were inverse predictors of sOB-R. With respect to the distribution of leptin in relationship to sOB-R levels (Fig. 2A), some surprising and interesting observations became evident: the majority of subjects with leptin levels less than 10 ng/ml (corresponding to the 75th percentile of all leptin data) also had sOB-R levels below the 75th percentile of all sOB-R data (<60 ng/ml). Within this subgroup no relationship between sOB-R and leptin was detectable (r = -0.098, P > 0.05). In contrast, almost all subjects with leptin levels above 10 ng/ml (>75th percentile) demonstrated normal or low levels of sOB-R (<60 ng/ml) and vice versa, subjects with sOB-R levels of 60 ng/ml or greater had normal or low leptin concentrations (<10 ng/ml). Qualitatively comparable data were found for the association between sOB-R and IGF-I (Fig. 2B): subjects with IGF-I levels above the 25th percentile of all IGF-I data (> 200 ng/ml) almost exclusively had normal or low levels of sOB-R (<60ng/ml). Again, subjects with sOB-R levels more than 60 ng/ml demonstrated nearly exclusively IGF-I levels in the range less than 200 ng/ml.
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Changes of the FLI compared with total leptin levels during childhood and adolescence are shown in Fig. 3. The courses of median values for leptin and FLI were found to be nearly parallel in both sexes. In boys the levels of leptin and FLI were significantly higher in the first phase of puberty compared with both early childhood and adolescence. In contrast, girls demonstrated the significantly lowest level of both parameters throughout the stage of prepuberty. Afterward, leptin and FLI increased gradually. Correlation analyses between FLI and leptin levels, respectively, and auxological and biochemical parameters are presented in Table 3. For nearly all parameters the coefficients of correlation were higher for the FLI than for the absolute leptin level. In girls these differences were even significant for the relationships with age, height, weight, BMI, puberty, and IGF-I. Only the three skinfold measurements were correlated rather to a stronger extent with leptin levels compared with FLI.
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In a small cohort of patients with anorexia nervosa a mean weight gain of 6.01 ± 0.75 (SD) kg (range 4.8–7.4) resulted in a significant increase in leptin levels (median 0.92 vs. 2.55 ng/ml, P < 0.01), whereas the median of sOB-R values decreased from 47.7 to 35.8 ng/ml (P < 0.01, Fig. 4).
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Discussion
This is, to our best knowledge, the first comprehensive investigation of serum sOB-R levels throughout childhood, puberty, and adolescence.
The majority of clinical studies performed so far report total leptin serum concentrations based on RIA measurements despite evidence that leptin binding activity is present in the peripheral blood. Thus, leptin circulates not only in its free form, but also in a complexed form with the sOB-R, which has been identified by our group to be the main leptin binding activity (17). As the averaged binding affinity of the sOB-R for leptin is in the same range as the binding affinity of leptin for its membrane receptor, the soluble form is capable of modulating leptin’s action (17, 18, 25). This modulation may occur via different mechanisms. First, excess of sOB-R may inhibit leptin binding to membrane receptors by competing directly with its ligand. Second, the sOB-R may remarkably delay the clearance of leptin by binding leptin (27). The latter has been proven in rats, where the half-life of leptin-sOB-R complexes is almost 20-fold longer compared with that of the free hormone (28).
To describe the potential modulating effects of sOB-R on leptin, it was necessary to establish a suitable and reliable method for quantification. Previously published methods used to determine leptin binding activity were based exclusively on the estimation of bound leptin, without considering the molecular identity of the binding moiety (18, 19, 20, 21, 22). Because it cannot be excluded that proteins other than sOB-R may compete for leptin binding, these assays may have a prejudiced specificity (29, 30). Additionally, endogenous leptin may also bias the respective results by competition for the binding sites.
The principle of our ligand immunofunctional assay includes the interaction between the sOB-R antigen and a specific antibody as well as the functional ability of sOB-R to bind its ligand. Leptin itself does not relevantly interfere with this assay. The consideration of the binding properties of sOB-R in a test system is of considerable importance, as sOB-R circulates in different isoforms that may have different affinities for the ligand leptin (17). Differences in the binding affinity between leptin and OB-R at different ages may also be relevant with regard to the biological action of leptin. It could be hypothesized that, during development, differences in glycosylation or a differential processing of the receptor may occur and hence, binding behavior and function of the receptor may change over time. However, there are no data available in the literature to substantiate this assumption.
To provide insights into the physiological role of sOB-R, the question as to whether or not leptin has a direct impact on the regulation of sOB-R needs to be addressed. Interestingly, the levels of sOB-R were relatively high during the first years of life and decreased significantly during late childhood and prepuberty in both sexes. This reduction is in agreement with data of Quinton et al. (31), who measured leptin binding activity in a small number of children elder than 5 yr. In contrast to the course of sOB-R values, leptin levels of our subjects remained nearly unchanged during the stage of prepuberty (data not shown). Thus, the high levels of sOB-R during early childhood may suppress leptin actions on its membrane receptor (32), at least in part. This mechanism supports a sufficient energy intake in the period of highest growth velocity. Afterward, during puberty, the decrease of sOB-R levels proceeded in both sexes in contrast to changes in leptin levels that follow a gender-specific pattern (Fig. 3
). Interestingly, high levels at the onset of puberty in boys are in accordance with previous findings (12). This is probably due to the influence of sex steroids on leptin production (33, 34). Our multiple regression analysis demonstrated that leptin was not an independent predictor for sOB-R. Additionally, the absence of correlations between skinfold thicknesses, as a surrogate measure of body fat mass and strong predictor of leptin levels, and sOB-R levels in the simple correlation analysis lead us to hypothesize that sOB-R appears to be not directly related to changes in leptin or body fatness.
On the other hand, because low levels of leptin were associated with normal or high levels of sOB-R and vice versa high levels of leptin were associated with low levels of sOB-R, an indirect relationship between the receptor and its ligand cannot be excluded. The regulation of sOB-R is presumably mediated by other parameters that could nevertheless be related to nutrition and energy metabolism. One candidate for such a mediator could be IGF-I. IGF-I is a major permissive factor for growth and in addition to GH action, IGF-I reflects the nutritional stage of a subject (35). In a teleological sense, IGF-I levels that are low during caloric restriction and that suppress cellular growth and support energy supply might ensure survival. In our study, height and its main determinant IGF-I as well as age were the most important independent variables underlying the variation of sOB-R in blood. Thus, during caloric restriction low IGF-I levels may induce an up-regulation of the OB-R at the level of the cell membrane. As the leptin binding activity of the OB-R and the level of sOB-R were found to be strongly correlated in cell culture experiments (36), OB-R up-regulation may lead to an increased shedding of its extracellular domain causing an increased binding of leptin in the peripheral blood. This posttranslational shedding process is the exclusive source of the sOB-R protein in humans where alternative splicing for sOB-R message, as shown in rodents, has been clearly excluded (37). Regulation and functional consequences of this process need to be investigated. In that manner, leptin action on its membrane receptor could be partially inhibited, and therefore, saturation and energy consumption would be suppressed. This mechanism may act to compensate unnecessary leptin action on energy deficiency.
The lines of evidence for a compensatory function of sOB-R were supported by our data from patients with anorexia nervosa, a condition with energy deficiency and hypoleptinemia (38, 39). High levels of sOB-R, which were again inversely associated with IGF-I values, may reflect the compensatory up-regulation of the sOB-R in the emaciated state to suppress undesired leptin action. During weight gain, increments of leptin as well as IGF-I levels and normalization or decrease of sOB-R levels occur. As a consequence, leptin action will gradually become more effective during weight gain. These changes of the leptin axis were obvious in all patients with elevated sOB-R levels in the emaciated state, whereas nearly no change of sOB-R on weight gain was observed in those patients with normal basal values of sOB-R. Additionally, leptin clearance in the peripheral blood is delayed by sOB-R (27). As leptin is one of several permissive factors, whose presence may be necessary to initiate sexual maturation (12), hypoleptinemia has to be avoided particularly during this phase of development. Increased sOB-R levels of subjects with hypoleptinemia may thus also represent a mechanism to temporally preserve the reduced hormone levels in the circulation. The duality of both effects induced by sOB-R, inhibition of leptin actions with its receptor and preservation of leptin clearance, is not fully understood so far. Possibly, the first effect may be relevant only in tissues, whereas the second could play a role in peripheral blood. Further studies will needed to evaluate this issue.
The physiological functions of bound and free leptin are also unclear to date. It has been hypothesized that leptin is more active in its free form, because this form is present in cerebrospinal fluid and may cross the blood-brain barrier easily (40). On the basis of this "free hormone is the biologically active hormone" hypothesis, it would be desirable to measure only the free leptin molecules. However, the exclusive quantification of the free hormone is difficult to accomplish, in part due to the fast dissociation of the leptin-sOB-R complex. A specific immunoassay based on an antibody against a leptin peptide has been described but is not fully validated so far (41). In accordance with the interpretation of data from other hormones whose action is modulated by binding proteins like T4 and testosterone (42, 43), we calculated the parameter FLI. To evaluate the usefulness of these calculated values, their relations with auxological and biochemical parameters were compared with the data of total leptin as measured by a conventional leptin RIA. As the curves of the median data for the FLI and the total leptin levels were nearly parallel during puberty, changes of total leptin seem to be preserved within this calculated parameter rather than changes of the sOB-R values. However, correlation analysis demonstrated that in particular the parameters of growth and sexual maturation are more closely related to the FLI than to leptin alone, predominantly in boys. On the other hand, the correlation of parameters reflecting body fat remained unchanged, independently if leptin or FLI were investigated. If one hypothesizes that the FLI reflects indeed the level of free leptin, then it is assumable that sOB-R modulates the function of leptin during childhood and adolescence. This finding may be of diagnostic interest and of biological relevance.
In conclusion, during childhood and adolescence, serum sOB-R levels show a characteristic decrease independent of gender, but are significantly inversely related to age, stage of puberty, and IGF-I. High levels of sOB-R in emaciation mirror a compensatory up-regulation of the sOB-R that may lead to a suppression of leptin actions. The FLI calculated as the ratio between leptin and sOB-R may be a new interesting parameter to describe physiological actions of leptin and has to be intensively examined in further studies involving patient groups with metabolic disorders. Therefore, methods for the determination of sOB-R are a further valuable tool to investigate the leptin axis during growth, sexual maturation, and specific metabolic conditions.
Acknowledgments
We express our sincere gratitude to Drs. A. Reich and K. Deutscher and to Ms. H. DePaly for their help in collecting sera as well as to Ms. K. Liebig for technical assistance. We are grateful to the families, children and adolescents for their understanding and participation.
Footnotes
This work was supported by the Bundesministerium fuer Bildung und Forschung (BMB+F), Interdisciplinary Centre for Clinical Research at the University of Leipzig, project B15, Leipzig, Germany. Ascertainment of patients with anorexia nervosa was supported by the Deutsche Forschungsgemeinschaft.
Abbreviations: BMI, Body mass index; FLI, free leptin index; sOB-R, soluble leptin receptor.
Received January 7, 2002.
Accepted June 26, 2002.
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