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Leptin Concentration in Cord Blood Correlates with Intrauterine Growth¹

Departments of Medicine (H.A.K., V.A.K., K.K., L.O.), Pediatrics (S.A.), Obstetrics and Gynecology (S.A., K.A.T.), and Clinical Chemistry (S.-L.K.), Helsinki University Central Hospital, Helsinki, Finland

Address all correspondence and requests for reprints to: Heikki Koistinen, M.D., Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland. E-mail: heikki.koistinen{at}helsinki.fi

	Abstract

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Leptin is an adipocyte-derived peptide hormone regulating energy balance in experimental animals. Although the physiological function of leptin in humans is still unclear, its secretion is closely related to fat mass in adult humans. To examine how fetal growth correlates with leptin levels at birth, an umbilical cord venous blood sample was obtained at the delivery from 50 term newborn infants. Twenty-eight of the newborn infants had birth weights appropriate for gestational age (AGA; mean ± SEM, 3362 ± 90 g; relative birth weight, -0.08 ± 0.2 SD), 9 were large for gestational age (birth weight, 4655 ± 165 g; relative birth weight, 3.2 ± 0.3 SD; P < 0.001 vs. AGA newborn infants), and 13 were small for gestational age (SGA; birth weight, 2385 ± 69 g; relative birth weight, -2.2 ± 0.08 SD; P < 0.001 vs. AGA newborn infants). Leptin concentrations were higher in large for gestational age (35.7 ± 8.0 µg/L; P < 0.005), but lower in SGA (3.3 ± 0.5 µg/L; P < 0.001) than in AGA infants (14.5 ± 2.8 µg/L). When adjusted for differences in body weight, mean leptin levels were similar in the three newborn groups. Leptin concentration correlated closely with both absolute and relative birth weights (r = 0.71; P < 0.001 in both), with cord blood insulin concentration (r = 0.67; P < 0.001), and with placental weight (r = 0.60; P < 0.001). These data suggest that leptin is synthesized in utero, and that the circulating leptin concentration relates to the intrauterine growth pattern.

	Introduction

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LEPTIN IS an adipocyte-derived peptide hormone that regulates energy balance in experimental animals (1, 2). Leptin levels reflect body fat content in mice (3) and humans (4, 5). The leptin concentration is associated with total energy expenditure and the level of physical activity in 5-yr-old children (6), suggesting a role for leptin in energy metabolism in man also. A majority of leptin research in humans has so far focused on adults. In a recent preliminary report, leptin was detectable in cord blood at birth, and it correlated with birth weight (7). The present study was undertaken to examine further how different intrauterine growth patterns relate to leptin secretion in utero.

	Subjects and Methods

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Newborn infants

We studied 50 newborn infants (27 females and 23 males; gestational age, 37–42 weeks; Table 1). They were not consecutive, but were selected to cover a wide range of birth sizes. To minimize possible effects of labor, a majority (40 of 50) were chosen from a newborn population delivered by cesarean section. Infant size was determined by reference to a Finnish newborn population of 74,766 singletons born between 1978–1982. Using infant birth weight, gestational age, and sex, each newborn infant’s relative birth weight was expressed in SD units (8). Twenty-eight newborn infants had birth weight appropriate for gestational age (AGA; relative birth weight below +2 or above -2 SD), 9 infants were large for gestational age (LGA; relative birth weight, +2 or more SD), and 13 were small for gestational age (SGA; relative birth weight, -2 or less SD). The study was approved by the ethical committee of the Department of Obstetrics and Gynecology of Helsinki University Central Hospital.

A blood sample from the umbilical vein was obtained after double clamping of the umbilical cord at birth. An amniotic fluid sample was obtained by amniocentesis from 10 mothers within 1–8 days before delivery and from 20 mothers at the cesarean section. An amniotic fluid sample was not taken from the mothers of the SGA infants.

Measurements

Umbilical vein leptin concentrations were determined by RIA (Linco Research, St. Charles, MO) (9, 10). For measurement of amniotic fluid leptin concentrations, the same assay was slightly modified by adding bovine -globulin in the precipitation reaction in the last incubation step. Free insulin concentrations were determined by RIA (Pharmacia, Uppsala, Sweden) (11).

Statistical analysis

Wilcoxon’s and Mann-Whitney U tests were used in the comparisons between paired and unpaired items, respectively. Correlation analysis was performed with Spearman’s test. Comparisons among the three newborn groups were made using ANOVA and analysis of covariance followed by post-hoc test with Bonferroni’s adjustment. Leptin and insulin concentrations were log transformed to normalize the distribution before ANOVA, analysis of covariance, and multiple regression analysis. All calculations were made using the Systat statistical package (Systat, Evanston, IL). The results are given as the mean ± SEM. P < 0.05 was considered statistically significant.

	Results

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Umbilical vein leptin concentrations were 146% higher in the LGA newborn infants (35.7 ± 8.0 µg/L; P < 0.005), but 78% lower in the SGA newborn infants (3.3 ± 0.5 µg/L; P < 0.001), than in the AGA newborn infants (14.5 ± 2.8 µg/L; Fig. 1). The differences in mean leptin concentrations among AGA, LGA, and SGA newborn infants vanished when leptin concentrations were adjusted for differences in the absolute (P = 0.327) or relative (P = 0.401) birth weight.

View larger version (10K): [in this window] [in a new window]   Figure 1. Leptin concentrations in SGA (P < 0.001 vs. AGA), AGA, and LGA (P < 0.005 vs. AGA) newborn infants.

Cord blood leptin concentrations correlated closely with both absolute (r = 0.71; P < 0.001) and relative (r = 0.71; P < 0.001; Fig. 2) birth weights, with birth length (r = 0.53; P < 0.001), with cord blood insulin concentrations (r = 0.67; P < 0.001), with placental weight (r = 0.60; P < 0.001), and with amniotic fluid leptin concentrations (r = 0.48; P < 0.01) when all newborn infants were analyzed together. In multiple regression analysis, the correlation of leptin with insulin remained significant when relative (partial correlation, 0.37; P < 0.02) or absolute (partial correlation, 0.43; P < 0.003) birth weights were accounted for.

View larger version (13K): [in this window] [in a new window]   Figure 2. Correlation between cord blood leptin concentration and relative birth weight in newborn infants (r = 0.71; P < 0.001).

	Discussion

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Our data indicate that fetal leptin concentrations are similar to those in adults (4, 10), and suggest that leptin synthesis occurs in utero. In addition, the high leptin levels in LGA and the low concentrations in SGA infants are possibly due to greater fat mass in LGA and lower fat mass in SGA infants (12). The strong correlation between leptin concentration and birth weight probably reflects the close relationship between birth weight and body fat mass in newborn infants (13).

As in cross-sectional studies in adult subjects (4, 10, 14), a close positive correlation between circulating leptin and insulin concentrations was observed in newborns in the present study. This was independent of birth weight, which suggests a direct contribution of insulin to leptin secretion. In adult humans, circulating leptin concentrations increase slightly during prolonged supraphysiological hyperinsulinemia (15).

There is a gender difference in adults, with females having higher concentrations of circulating leptin than males (5, 14). This has not been detected in all studies (4, 10), perhaps because leptin levels were adjusted for percent body fat, a bounded number, instead of total fat mass. The gender difference in leptin concentrations has also been demonstrated in prepubertal children (16). We detected no gender difference in leptin concentrations in the newborn infants. Moreover, at birth there is no gender difference in concentrations of PRL, estriol, or dehydroepiandrosterone sulfate (17), suggesting that at birth there are few, if any, hormonal gender differences in humans.

Kidneys account for 81% of the total leptin removal from the blood in the rat (18), and amniotic fluid is mainly produced by fetal kidneys during the latter half of pregnancy. The amniotic fluid leptin concentrations in our study were of the same magnitude as those recently reported (7) and were slightly higher in LGA than AGA newborns. The serum to amniotic fluid leptin concentration ratio was similar in the LGA and AGA infants. These data suggest that fetal kidneys secrete leptin into the amniotic fluid in proportion to the prevailing serum levels.

In conclusion, leptin secretion probably occurs in utero. The strong correlation between body weight and leptin concentration at term suggests that adipose tissue mass is a major determinant of leptin secretion in utero.

	Acknowledgments

 
The excellent technical assistance of Ms. E. Kostamo, Ms. T. Kyöstiö-Renvall, and Ms. Hilkka Puttonen is appreciated.

	Footnotes

 
¹ This work was supported by the Yrjö Jahnsson Foundation, the Finnish Academy of Science, Paulo Foundation, Novo Nordisk Foundation, the Finnish Medical Foundation, and the Clinical Research Institute of Helsinki University Central Hospital.

Received March 31, 1997.

Revised May 7, 1997.

Accepted June 18, 1997.

	References

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1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. 1994 Positional cloning of the mouse obese gene and its human homologue. Nature. 372:425–432.[CrossRef][Medline]
2. Pelleymounter MA, Cullen MJ, Baker MB, et al. 1995 Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 269:540–543.[Abstract/Free Full Text]
3. Frederich RC, Hamann A, Anderson S, Löllmann B, Lowell BB, Flier JS. 1995 Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1:1311–1314.[CrossRef][Medline]
4. Considine RV, Sinha MK, Heiman ML, et al. 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 334:292–295.[Abstract/Free Full Text]
5. Rosenbaum M, Nicolson M, Hirsch J, et al. 1996 Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab. 81:3424–3427.[Abstract]
6. Salbe AD, Nicolson M, Ravussin E. 1997 Total energy expenditure and the level of physical activity correlate with plasma leptin concentrations in five-year-old children. J Clin Invest. 99:592–595.[Medline]
7. Schubring C, Kiess W, Englaro P, Rascher W, Blum W. 1996 Leptin concentrations in amniotic fluid, venous and arterial cord blood and maternal serum: high leptin synthesis in the fetus and inverse correlation with placental weight [Letter]. Eur J Pediatr. 155:830.[Medline]
8. Pihkala J, Hakala T, Voutilainen P, Raivio K. 1989 Uudet suomalaiset sikiön kasvukäyrät. Duodecim. 105:1540–1546.[Medline]
9. Ma Z, Gingerich RL, Santiago JV, Klein S, Smith CH, Landt M. 1996 Radioimmunoassay of leptin in human plasma. Clin Chem. 42:942–946.[Abstract/Free Full Text]
10. Rönnemaa T, Karonen S-L, Rissanen A, Koskenvuo M, Koivisto VA. 1997 Relation between plasma leptin levels and measures of body fat in identical twins discordant for obesity. Ann Intern Med. 126:26–31.[Abstract/Free Full Text]
11. Desbuquouis B, Aurbach GD. 1971 Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassays. J Clin Endocr. 33:732–738.
12. Enzi G, Zanardo V, Caretta F, Inelmen EM, Rubaltelli F. 1981 Intrauterine growth and adipose tissue development. Am J Clin Nutr. 34:1785–1790.[Abstract/Free Full Text]
13. Lapillonne A, Braillon P, Claris O, Chatelain PG, Delmas PD, Salle BL. 1997 Body composition in appropriate and in small for gestational age infants. Acta Paediatr. 86:196–200.[Medline]
14. Saad MF, Damani S, Gingerich RL, et al. 1997 Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab. 82:579–584.[Abstract/Free Full Text]
15. Utriainen T, Malmström R, Mäkimattila S, Yki-Järvinen H. 1996 Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes. 45:1364–1366.[Abstract]
16. Hassink SG, Sheslow DV, de Lancey E, Opentanova I, Considine RV, Caro JF. 1996 Serum leptin in children with obesity: relationship to gender and development. Pediatrics. 98:201–203.[Abstract/Free Full Text]
17. Yuen BH, Mincey EK. 1987 Human chorionic gonadotropin, prolactin, estriol, and dehydroepiandrosterone sulfate concentrations in cord blood of premature and term infants: relationship to the sex of the neonate. Am J Obstet Gynecol. 156:396–400.[Medline]
18. Cumin F, Baum H-P, Levens N. 1996 Leptin is cleared from the circulation primarily by the kidney. Int J Obes. 20:1120–1126.[Medline]

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