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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1454
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2212-2217
Copyright © 2005 by The Endocrine Society

Inverse Changes in the Serum Levels of the Soluble Leptin Receptor and Leptin in Neonates: Relations to Anthropometric Data

J. Kratzsch, C. Schubring, B. Stitzel, A. Böttner, A. Berthold, J. Thiery and W. Kiess

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital, Faculty of Medicine (J.K., J.T.), D-04103 Leipzig, Germany; Evangelisches Krankenhaus (C.S., B.S.), D-35398 Giessen, Germany; and Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig (A.Bo., A.Be., W.K.), D-04317 Leipzig, Germany

Address all correspondence and requests for reprints to: Dr. Juergen Kratzsch, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, Paul List Strasse 13–15; D-04103 Leipzig, Germany. E-mail: kraj{at}medizin.uni-leipzig.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We aimed to evaluate the role of the soluble leptin receptor (sOB-R), the major leptin-binding protein in blood, for the regulation of growth and development of neonates. Therefore, human arterial and venous cord blood samples were taken from newborns of 45 healthy mothers to investigate correlations with anthropometric data. Furthermore, we compared changes in sOB-R and leptin in neonatal serum between postnatal d 1, 3, and 5. Cord blood levels of leptin (direct correlation) and the molar sOB-R/leptin ratio (inverse correlation) correlated significantly (P < 0.05) with weight, triceps, biceps, iliacal, and subscapular skinfolds at birth as well as on d 3 and 5 of life. During the first week of life, median leptin levels decreased significantly (P < 0.001) from 3.4 ng/ml in venous cord blood to 2.2 ng/ml in venous blood on d 1 after birth to 0.88 ng/ml on d 3 and 0.75 ng/ml on d 5. In contrast and most interestingly, median levels of sOB-R increased significantly (P < 0.001) from 14.5 ng/ml in cord blood to 18.9 ng/ml on d 1, 83 ng/ml on d 3, and 79.4 ng/ml on d 5. Consequently, the molar sOB-R/leptin ratio increased from 0.45 to 1.30 (d 1), 10.5 (d 3), and 13.7 (d 5) during the same period (P < 0.001). We found a remarkable postnatal change in the leptin-sOB-R axis with decreasing leptin and increasing sOB-R levels. Hence, the sOB-R may block leptin function by its competition with the membrane receptor for the ligand. These suppressive effects may be an important stimulus for energy uptake in the first week of life or in other conditions with a high energy demand.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DURING GESTATION, THERE is a tremendous increase in body fat mass in both the mother and, particularly during the third trimester, the fetus. The mechanisms by which maternal and fetal weight and fat mass are regulated during pregnancy are poorly understood. Immediately after birth, adipose tissue has an important role in providing the newborn with energy substrates after the challenge of acute loss of energy supply by the maternal-fetal circulation. Therefore, adipose tissue is highly sensitive to regulating factors that stimulate the release of fatty acids and glycerol into the circulation and for the suppression of triglyceride formation (1). Moreover, the adipose tissue of the newborn not only responds avidly to hormonal stimuli, but has been recognized to synthesize and secrete hormonal factors, providing feedback loops between fat tissue and endocrine glands. One of these important factors is leptin, the adipose tissue-derived hormone that decreases food intake and increases body temperature and energy expenditure (2, 3, 4). Leptin levels are high at term and correlate with birth weight (5, 6, 7). They decline rapidly and dramatically after birth, and this decline might be an important stimulus for the onset of feeding or energy uptake (7).

The soluble leptin receptor (sOB-R) represents the main leptin-binding activity in human blood (8). This protein circulates in two different N-glycosylated isoforms as a dimer or in an oligomerized state. Complexes of leptin with sOB-R reflect a molecular ratio of 1:1 (9). In mice, alternative splicing results in different leptin receptor variants, including its soluble isoform (10). Additionally, the sOB-R was shown to be generated by ectodomain shedding of membrane-bound receptor forms (11). Experimental data in humans provide evidence that sOB-R is produced similarly by a metalloprotease-mediated cleavage (12). In contrast to rodents, no human mRNA for a splice form encoding the soluble leptin receptor has been detected to date (13). The functional soluble receptor isoform potentially modulates steady-state leptin levels by complexing free leptin in the circulation and consequently preventing the hormone from degradation and clearance (14, 15). Therefore, high sOB-R levels in blood, as determined in lean or anorectic humans (16, 17), may act as a potential reservoir of bioactive leptin. Furthermore, recently published data by Yang et al. (18) and by our group (19) demonstrated that a 2-fold or greater excess of sOB-R can suppress leptin action in a cell model. Thus, sOB-R excess may play a role in the development or progression for at least partial leptin resistance in peripheral tissues.

In our study we evaluated the role of sOB-R, the major leptin-binding protein in blood, in the growth and development of neonates. Blood samples were taken at birth from arterial and venous cord blood to investigate correlations with anthropometric data of the neonates. Furthermore, we compared changes in sOB-R and leptin in neonatal serum on postnatal d 1, 3, and 5, a period of dramatic weight loss and metabolic alterations in the infant.


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

Forty-five healthy mothers who gave birth to one healthy newborn at Evangelisches Krankenhaus (Giessen, Germany) were included in the study. Clinical and anthropometric data of newborns and mothers at birth are summarized in Table 1Go. All pregnancies were without complications; all newborns and mothers were healthy and did not require special medical attention after birth. Informed consent was obtained from all mothers. Approval from the ethical committee of University of Giessen had been obtained before the start of the study. Skinfolds were measured at four sites (iliacal, subscapular, biceps, and triceps) using a Holtain caliper (Holtain Ltd., Crymych, UK) by one investigator (B.S.). Clinical and anthropometric data were recorded using a standardized data report form by one investigator (B.S.).


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  		TABLE 1. Clinical, anthropometric, and biochemical data of the investigated mothers (n = 45) and children at term are summarized

 
Blood sampling

Maternal blood was obtained from a cannulated vein directly after birth. Venous and arterial cord blood was drawn immediately after birth from the umbilical blood vessels by one investigator (C.S.). Three additional fasting blood withdrawals were performed from the antecubital vein on d 1 (2–3 h after birth), 3, and 5 after birth between 0600 and 0800 h, respectively. Sera were obtained by centrifugation at 4 C, immediately frozen, and stored at –20 C until additional analysis. Volumes of milk were determined by weighing the neonates before and after one meal at night and were extrapolated for the number of milk ingestions in 24 h. Actual n values for blood withdrawals and milk volumes are given for the specific measurements as indicated.

Laboratory methods

sOB-R. The concentration of sOB-R was determined by an in-house ligand immunofunctional assay, as recently described (17). The lowest detectable sOB-R concentration in the assay was calculated to be less than 2.0 ng/ml. Intra- and interassay coefficients of variation for two control samples were lower than 11.7% (n = 10).

Leptin. Leptin was measured by an in-house RIA (20). Its intra- and interassay coefficients of variation were lower than 12.5% in the range from 1–8 ng/ml leptin. The recovery of dilution experiments was 88–112% for the concentration range of 4–6 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).

sOB-R/leptin ratio. This ratio has been calculated to estimate the molar relationship between sOB-R (130 kDa) and leptin (16 kDa) by calculating this quotient, multiplied by 0.13 to correct the difference in their molecular masses.

Statistical analysis

Statistical analysis was performed using the Statistica 6.0 (Statistica, Inc., Tulsa, OK) program. In general, data were expressed as mean ± SD. Because leptin levels were not normally distributed, nonparametric statistic tests (median, quartile range, Spearman’s correlation, and Kruskal-Wallis ANOVA, as indicated) were used to analyze the biochemical data.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Leptin axis of mothers and newborns at birth

Detailed parameters of the leptin axes of mothers and newborns are demonstrated in Table 2Go. In the correlation analysis for maternal and neonatal data, there was only a trend between leptin levels in arterial or venous blood with placental weight (P < 0.10). There was no significant correlation between any clinical, anthropometric, or biochemical data of mothers with any parameter of the leptin axis of newborns.


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  		TABLE 2. Comparison of the leptin axis from mothers (n = 25) and newborns (11 boys and 18 girls)

 
In the newborns, median [quartile] leptin levels were significantly higher in venous (3.40 [4.00] ng/ml) compared with arterial (2.79 [3.41] ng/ml) blood (n = 32; P = 0.029). In contrast, the sOB-R concentrations of both blood samples were nearly identical (arterial, 15.4 [12.5]; venous, 14.4 [10.9] ng/ml). No significant difference was detectable for the levels of leptin and sOB-R between male and female newborns.

Dynamics of leptin axis and anthropometric parameters of newborns in the postnatal period

Table 3Go shows the significant decreases in body weight and skinfold measures during the first 5 d of life. These changes were accompanied by remarkable alterations in leptin, sOB-R levels, and molar sOB-R/leptin ratio in serum (Fig. 1Go). Leptin (median [quartile range]) significantly decreased during the first days of life in venous cord blood from 3.4 [4.4] ng/ml to a level of 2.2 [4.9] ng/ml in venous blood on d 1 after birth to 0.88 [0.40] ng/ml on d 3 and 0.75[0.77] ng/ml on d 5 (Fig. 1AGo). In contrast and most interestingly, levels of sOB-R (median [quartile range]) increased significantly (P < 0.001) from cord blood (14.5 [10.4] to d 1 (18.9 [19.4] ng/ml) to d 3 (83.0 [53.3] ng/ml) and d 5 (79.4 [22.4] ng/ml; Fig. 1BGo). This distinct pattern resulted in a pronounced net increase in the molar sOB-R/leptin ratio (Fig. 1CGo), which was 13.7 [13.8] on d 5 and, therefore, 30-fold higher compared with birth. Although the leptin levels showed a considerable variation between individuals on the first day of life, levels of sOB-R and the molar sOB-R/leptin ratio showed a distinct scatter on the third and fifth days after birth.


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  		TABLE 3. Descriptive statistics for changes of anthropometric parameters and milk volume ingested by the neonates evaluated on d 1, 3, and 5 after birth

 


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  		FIG. 1. Differences between levels of leptin (A), sOB-R (B), and the molar ratio between sOB-R and leptin (C) in neonates depending on age. Data are expressed as median (squares), quartiles (boxes), and range (whiskers). The actual number of available datasets for the comparison of the investigated parameters was 35 for cord blood, 18–27 for venous blood on d 1, 17–24 for d 3, and 14–17 for d 5. The asterisk in panel A represents an outlying data point.

 
Are parameters of the leptin axis at birth associated with anthropometric changes in the first days of life?

Arterial as well as venous blood levels of leptin (direct correlation) and the sOB-R/leptin ratio (inverse correlation) were significantly correlated with body weight and triceps, biceps, iliacal, and subscapular skinfolds at birth, d 3, and d 5 (Table 4Go). In contrast, arterial sOB-R levels revealed a weak inverse correlation with the subscapular skinfold value on d 1 and 3 after birth. All in all, the coefficients of correlations from arterial cord blood appear to be higher than venous blood measurements. Interestingly, the amount of milk ingested by the neonate on d 3 and 5 was directly correlated with leptin levels and the sOB-R/leptin ratio as well as indirectly with the sOB-R levels measured in cord blood.


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  		TABLE 4. Correlations according to Spearmann between parameters of the leptin axis in cord blood and placental weight as well as anthropometric data of the newborns

 
Leptin levels at birth correlated with leptin levels on d 1 (r = 0.57; P < 0.05), but these data were not predictive of leptin concentrations on d 3 or 5 (P > 0.10). However, sOB-R levels at birth (n = 20) correlated with sOB-R data on d 1 (r = 0.56; P = 0.01) and d 3 (r = 0.62; P = 0.008), but not with data on d 5 (r = –0.15; P = 0.67). There were no significant correlations between sOB-R and leptin during this period.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study characterizes the dynamics of the leptin axis during the first days of life, which is reflected by an excessive increase in the ratio of sOB-R to leptin. This is of potential importance because the newborn infant experiences a dramatic physiological reduction of body weight during this first week of life due to physiological fluid loss and reduced nutritional intake (21).

We were able to show that the sOB-R is, like leptin itself, present in maternal serum and cord blood at birth. Because there was no correlation between maternal sOB-R serum concentrations and sOB-R levels in cord blood, we conclude that the latter is derived from fetal tissues, similar to leptin. As recently shown (22), leptin levels in newborns were significantly higher in venous compared with arterial cord blood, suggesting that leptin expressed by the placenta may be secreted into the circulation. In contrast, sOB-R levels were independent from the blood withdrawal site; therefore, the placenta appears to be no major additional source of sOB-R in the fetus.

To date, sOB-R levels in cord blood have not been evaluated in detail. Our study suggests that levels of this protein at birth are independent of gender and are comparable with serum levels in adolescents (17). Quinton et al. (23) determined adulthood-like leptin-binding activity in 10 cord blood sera. Even though leptin-binding activity is an uncertain surrogate marker for sOB-R protein, this finding supports our sOB-R data at birth (23).

A putative role for free leptin as an important regulator of maternal and fetal weight and intrauterine growth is suggested from the literature (5, 6). Our findings of highly significant correlations between cord blood levels of the leptin axis and birth weight support this concept. Although leptin is a highly significant direct predictor of weight and skinfolds at birth, sOB-R, in contrast, appears to be only weakly regulated and demonstrated an inverse correlation with these growth parameters, suggesting a different regulation from leptin. However, it is known that leptin and its soluble receptor constitute a well-regulated system (24). Alterations in either of the two components result in changes in the net biological activity of leptin, with effects on the physiological processes of the body. An optimal fetal leptin axis, reflected in part by the leptin axis in cord blood, appears to be a very important precondition for growth and development during the first days of life. This argument is underlined by the high predictive value of leptin levels and sOB-R/leptin ratios for the changes in weight and skinfolds as well as for milk intake until d 5 of life, suggesting a direct relationship to the nutrition of the neonate. The markedly higher coefficients of correlations between anthropometric changes and parameters of the leptin axis measured in arterial compared with venous blood may be a clue to why arterial blood reflects the signal of fetal energy deficiency rather than mixed venous blood originating from the placenta.

The first 5 d of life are characterized by dramatic changes in regulation of the leptin axis. The relatively high leptin levels in arterial and venous cord blood suggest that the fetus expresses high levels of the ob gene product at term. It is conceivable that high levels of leptin provide a signal of satiety around birth and thus suppress appetite during labor and delivery. The subsequent sudden fall in leptin levels to a median of 22% on the fifth day of life may be due to the above-mentioned loss in body weight and may provide a major stimulus for appetite and the initiation of feeding (7). This change in leptin levels is accompanied by the uncoupling of associations between leptin and parameters of body weight suggesting the presence of a different regulative mechanism. Our findings of elevated sOB-R levels (5.5-fold between delivery and d 5 of life) as well as sOB-R/leptin ratios (30.3-fold) at the same time points support the above-mentioned hypothesis. According to data from our recently published in vitro cell model (19), fetal leptin at term should be bioactive, because the molar sOB-R excess is clearly less than 2. In contrast, the elevation of sOB-R and the reduction of leptin levels during the first days of life lead to a dramatic increase in the molar sOB-R/leptin excess, with a median level of 14 (maximum, 60.6). This is the highest molar excess of sOB-R over leptin in blood observed in humans to date and may very efficiently suppress leptin action. This mechanism can, in fact, lead to clearly reduced leptin bioactivity, because a 10-fold molar excess of sOB-R was associated with an approximately 70% reduced bioactivity of leptin, as shown by the in vitro model (19). The finding reported by Hytinantti et al. (25) that free leptin levels, measured after HPLC separation, decreased from birth to 3 d of life supports our observation. Thus, the inverse regulation of leptin and sOB-R may favor the urgently needed energy uptake to compensate for the weight loss during the first days of life. Additionally, because leptin is known to affect immune function (26), lower leptin bioactivity could partially explain the decreased immune function of infants. In contrast, increased sOB-R levels may prevent unproportional loss of leptin (15, 27), which may be of importance considering peripheral actions of leptin such as its effects on growth and differentiation (for a review, see Ref. 28). Therefore, the suppressive effect of sOB-R on the biological action of leptin in states of energy deficiency is unlikely to be restricted to the central effects of leptin as a satiety factor.

The question of which regulator may induce this compensatory mechanism of the leptin axis is also of interest. No clear experimental evidence for such a role of leptin has been published. However, weight loss may be related to the induction of sOB-R synthesis. This hypothesis is supported by our data and underlines the role of sOB-R as a compensatory regulator for energy deficiency and as a secondary influencing factor within the leptin axis. Anorexia nervosa is a comparable condition characterized by weight loss and reduced leptin levels (29, 30). High levels of sOB-R, which were inversely associated with IGF-I values, reflected here a compensatory up-regulation of the soluble leptin receptor in the emaciated state, aimed at suppressing undesired leptin action (17). During weight gain, elevations of leptin as well as IGF-I levels and a decrease in sOB-R levels occurred. As a consequence, net leptin action gradually became more effective. The molecular mechanism for increased sOB-R is unclear. Therefore, it is possible that induction of a metalloprotease (11, 12), perhaps in the liver as part of a general stress response, could lead to the increased cleavage and shedding of sOB-R.

In conclusion, the biological action of leptin is controlled by its soluble receptor dependent on certain metabolic or developmental conditions. At a molar excess of the sOB-R, suppressive effects on leptin action may be important for energy uptake in conditions with a high energy requirement, such as during the first days of life.


   Acknowledgments
 
The help of technical assistants E. Jaeschke and Ch. Liebig in performing the biochemical analyses is appreciated.


   Footnotes
 
This work was supported by grants from the Interdisciplinary Center for Clinical Research at the University of Leipzig, Project B15 (to J.K.).

First Published Online January 25, 2005

Abbreviation: sOB-R, Soluble leptin receptor.

Received July 23, 2004.

Accepted January 17, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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