Abstract
Background. The hormone leptin, produced in the adipose tissue, is involved in the regulation of body weight. The release of the hormone is increased in obese adults and decreased after fasting in human adults. This study investigated whether the plasma leptin level was related to the infant's birth weight and whether the level was reduced in connection with the physiological weight loss during the neonatal period.
Methods. We measured the plasma leptin level in cord blood from infants who were large for gestational age (LGA) (n = 15), small for gestational age (SGA) (n = 16), and appropriate for gestational age (AGA) (n = 38). AGA infants (n = 120), who were exclusively breastfed, were also studied during their first 4 postnatal days in a cross-sectional method. One blood sample was collected before breastfeeding from each infant. Plasma leptin concentrations were determined by radioimmunoassay.
Results. The median (range) concentration of leptin from cord blood was increased in LGA infants and decreased in SGA infants compared with the level in AGA infants. There was a positive correlation between the log of the plasma leptin level in cord blood and both the infant's birth weight (r = 0.76; n = 69) and the body mass index (r = 0.63; n = 69). The normal 3% to 6% weight reduction that occurs during the first 4 postnatal days was associated with a 26% decrease in the plasma leptin level in healthy breastfed infants.
Conclusions. The plasma leptin level is highly correlated to the size of adipose tissue mass and decreases in connection with the initial physiological weight loss in newborn infants. These data provide evidence that leptin is highly related to the nutritional status already during the fetal and neonatal periods.
- LGA =
- large for gestational age •
- SGA =
- small for gestational age •
- AGA =
- appropriate for gestational age •
- SD =
- standard deviation •
- BMI =
- body mass index •
- NPY =
- neuropeptide Y
Leptin, the protein product of the ob gene produced in the adipose tissue, is involved in the body nutritional homeostasis through the control of appetite and energy expenditure.1 2 Circulating leptin concentrations are increased in obese children3 and adults4 5compared with those that are of normal weight. Furthermore, the expression of the ob gene is subject to nutritional regulation being markedly reduced after fasting both in humans4 and rats.6 7
This study was undertaken to investigate if leptin might be a regulator of nutritional state during fetal and neonatal life. Therefore, we examined whether leptin could be detected in plasma at concentrations that correlated with birth weight and whether plasma leptin concentrations were reduced in connection with the physiological weight loss in healthy, exclusively breastfed, newborn infants.
PATIENTS AND METHODS
The study was approved by the Local Ethics Committee of the Karolinska Hospital and the parents gave their informed consent. Seven groups of infants were studied, all delivered at term (gestational time, ≥37 weeks). Group 1 included infants that were large for gestational age (LGA) (n = 15); 12 of 15 were normal pregnancies and 3 of 15 had maternal type I diabetes. Group 2 included infants that were small for gestational age (SGA) (n = 16); 13 of 16 were normal pregnancies, beside the intrauterine growth retardation, 3 of 16 also had mild preeclampsia. Infants in Group 1 and Group 2 were delivered either with normal delivery or cesarean section. Group 3 included infants with birth weights appropriate for gestational age (AGA) (n = 38); these were all born after normal pregnancy and delivery. Birth weight was assessed on a digital scale and then evaluated according to Marsál et al.8 Neonates were classified as SGA or LGA if birth weight was below or greater than 2 standard deviations (SD) of mean gestational age-related intrauterine weight. Mean body mass index (BMI), defined as the weight in kilograms divided by the square of the length in meters, was calculated. See Table 1 for anthropometric and clinical data. Blood samples for the leptin determination were collected at delivery by double clamping the umbilical cord at the placental end and the infant end within 5 seconds after birth. In Group 3 one blood sample was also collected from the mothers (n = 17) within 10 minutes of delivery by puncture of an antecubital vein.
Antropometric and Clinical Data of the Study Populations*
To investigate the effect of weight loss on the leptin level, we also studied AGA infants (n = 120) during the first 4 postnatal days using a cross-sectional method; the cord level from AGA infants of Group 3 constituted the start measurement. These infants were all delivered after normal pregnancy and delivery and all had an uneventful neonatal period; they were exclusively breastfed on demand. As part of the study design, the mothers weighed their infants on a digital scale each morning. A blood sample for the leptin determination was randomly collected at a postnatal age of 16 ± 4 hours (mean ± SD) (n = 30; Group 4); when the infant was 1 day old (24 ≤ hours < 48) (n = 30; Group 5); when the infants were 2 days old (48 ≤ hours < 72) (n = 30; Group 6); and when the infants were 3 days old (72 ≤ hours < 96) (n = 30; Group 7). There was no systematic difference between the age groups as to maternal age, parity, infant's birth weight, or sex (for details, see Tables 1 and 2). Blood samples were always collected before a feeding, between 8 am and 2pm when the infant woke up spontaneously and displayed hunger signals. Hunger signals were defined as the presence of spontaneous rooting and/sucking movements and increased gross motor activity of the limbs eventually followed by crying. The interval from the previous feeding was recorded. Each infant contributed one blood sample collected from a vein on the back of the hand or from an antecubital vein with an open needle technique. Blood samples were collected in ice-chilled plastic tubes containing 10 IU heparin (Kabi AB, Stockholm, Sweden) and 500 IU aprotinin (Bayer AB, Stockholm, Sweden)/mL blood. Plasma was obtained by centrifugation at 4°C for 10 minutes and was then frozen at −70°C until the time of assay. Leptin concentrations were determined in plasma by a commercially available kit (Linco Research IMC, St Charles, MO). The limit of detection was 0.5 μg/L, the intraassay standard coefficient of variation was 3.9%, and the interassay coefficient of variation was 4.7% at the leptin concentration of 10.4 ± 0.5 μg/L.
Anthropometric and Clinical Data on the Study Populations*
Statistics
Clinical and anthropometric data of the study populations are given as mean ± SD. Because the plasma leptin concentrations followed a non-Gaussian distribution, these data are given as median (range) and we used the Mann-Whitney U test to evaluate possible differences in the plasma leptin concentrations from cord blood between LGA, SGA, and AGA infants. Multiple regression analysis was performed to evaluate the relation of the plasma leptin concentration to birth weight and BMI; leptin was plotted on a log scale, as the levels were not normally distributed. We used the Kruscal-Wallis rank test, followed by the Mann-Whitney Utest to evaluate possible differences in leptin concentrations in relation to postnatal age in AGA infants. Differences between maternal and umbilical cord levels in AGA infants were assessed by the Wilcoxon rank sum test.
RESULTS
The median (range) plasma leptin concentration in cord blood from LGA infants was 24.1 (10.0–71.0) μg/L as compared with 7.3 (1.8–32.1) μg/L in AGA infants (P < .001). The median leptin concentration in SGA infants was 2.6 (1.4–7.4) μg/L, which was significantly lower (P < .001) compared with the level in AGA infants. There was a positive correlation between the log of the plasma leptin concentration in cord blood and both the infant's birth weight (r = 0.76, n = 69, P < .001) and the BMI (r = 0.63, n = 69, P < .001) (see Fig 1). No significant relationship was found between gender and leptin cord level in LGA (P > .06), SGA (P > .1), or AGA infants (P > .4).
The relation between the log of the plasma leptin concentration and A) birth weight (r = 0.76; P < .001) and B) BMI (r = 0.63; P < .001) in 38 AGA infants, 15 LGA infants, and 16 SGA infants.
The median leptin concentration in cord blood from AGA infants was significantly lower (P < .01) than corresponding maternal levels in venous blood 20.0 (3.6–29.0) μg/L. There was no significant difference in the leptin concentration between arterial [5.2 (3.2–14.2) μg/L; n = 8] and venous cord blood [5.3 (2.6–17.5) μg/L; n = 8].
AGA infants lost 3% to 6% of their birth weight during the first 4 days after birth (Table 3). The infant's leptin concentration fell significantly at 16 ± 4 hours (mean ± SD) after birth compared with the level in umbilical cord blood (P < .001) and remained constantly low for the following 3 days (for details, see Table 3). Leptin levels were not significantly (P > .1) related to the duration of the interval between two subsequent feedings or to the degree of weight reduction during the 4 postnatal days (data not shown).
Plasma Leptin Concentrations and Weight Loss in Healthy Newborn Infants (n = 158) During Their First Four Days of Life*
There was a negative correlation between the leptin concentration and postnatal age during the first day of life (r = 0.38, P < .05, n = 30), but not at any other postnatal age.
DISCUSSION
We found that LGA infants had higher and SGA infants had lower leptin concentrations than AGA infants. The leptin concentration was highly correlated to both birth weight and BMI. Furthermore, we also found that the physiological neonatal weight loss was associated to a reduction of the plasma leptin level.
The leptin level in cord blood from AGA infants was comparable to that previously described in cord blood9 10 and to that found in both normal weight children3 and adults.5 The infants had, however, lower levels than their corresponding mothers; this is probably attributable to the pregnant woman's acquisition of adipose tissue. Furthermore, the cord level does not seem to be influenced by the birth process because we found no significant difference in leptin levels from cord blood between normal vaginal delivery and elective cesarean section (for details, see Fig2).
Plasma leptin concentrations from cord blood after normal vaginal delivery (n = 17) and after elective cesarean section (n = 17). All infants were delivered at term and their birth weight was appropriate for gestational age. Median and individual values are given. There was no significant difference in the leptin level between the two groups (P > .1, Mann-WhitneyU test).
LGA infants had threefold more plasma leptin than AGA infants; the level was comparable to that described in obese children (mean age, 11 years)3 and adults.5 SGA infants had only one-half as high hormone levels as AGA infants, presumably reflecting the reduced body fat content of these infants. Leptin is produced in the adipocytes and the leptin level is regulated by direct changes in the expression of the ob gene in both humans4 5and rodents.6 The hormone level is highly correlated to both BMI and percentage body fat in humans.5
We also found that the reduction of 3% to 6% of body weight that occurred during the first 4 postnatal days was associated with a reduction of 26% in plasma leptin in healthy breastfed infants. The newborn infant is subjected to a transitory period of reduced nutritional intake during the first few days after birth because lactation is not fully established so early after delivery. As a consequence of this, the infant exhibits a physiological reduction of body weight which, in average, is 5% to 6% of birth weight.11 Fasting is associated with a decrease in both the leptin level as well as the ob gene expression4in humans and rodents.6 One important site of action for leptin seems to be the ventromedial hypothalamic arcuate nucleus where it may interact with appetite-regulating systems, because the hormone decreases biosynthesis and secretion of neuropeptide Y (NPY), which is a potent stimulator of appetite.12 After only 4% of weight loss, there is a 43% reduction of arcuate NPY mRNA in mice, indicating a clear effect of leptin in reducing NPY gene expression.13The reduced intake of nutrients and fluid experienced by the infant during the first days after birth may constitute a signal to reduce leptin production so that appetite would not be inhibited; in fact, the behavior of the infants in this study, characterized by the presence of spontaneous hunger signals could have been affected by the reduced leptin expression. This signal may, at least in part, be working through a lowered insulin tone. Another physiological stimulus besides fasting that has been shown to affect the leptin level is cold exposure, which causes a decrease in both the leptin level14 and ob gene expression in rats.15 The reduction of the infant's body temperature, as a consequence of the extrauterine adaptation,16 could therefore also contribute to a the initial decrease in leptin secretion. Fasting and cold exposure are also accompanied by increased lipolysis and elevated levels of free fatty acids. Free fatty acids cause a concentration-dependent inhibition of leptin mRNA levels in cultured mouse adipocytes.17 The immediate neonatal metabolic adaptation characterized by a rapid onset of lipolysis with high levels of free fatty acid11 could be an adjunctive factor suppressing the leptin level. Because the hypothalamus integrates metabolic control, thermal homeostasis, and modulating feeding behavior through an extensive neuronal network,18 ob gene expression is probably affected by various physiological stimuli.
CONCLUSIONS
In summary, plasma leptin levels are increased in LGA infants and decreased in SGA infants. The level is directly proportional to adipose tissue mass. Furthermore, the normal neonatal weight loss is associated with an acute decrease in the leptin level, probably as a result of the extrauterine adaptation. Taken together, these findings indicate that leptin may participate in the regulation of nutritional homeostasis already present during fetal and neonatal life.
ACKNOWLEDGMENTS
This work was supported by grants from the foundations: Mjölkdroppen, Svenska Läkarsällskapet, Sällskapet Barnavård, KI-fonder, MFR 14X-57164.
Footnotes
- Received March 11, 1997.
- Accepted September 2, 1997.
Reprint requests to (G.M.) Department of Women and Child Health, Karolinska Hospital, 171 76 Stockholm, Sweden.
REFERENCES
- Copyright © 1998 American Academy of Pediatrics
In this issue
Jump to section
Related Articles
Cited By...
- Intrauterine growth restriction and adult disease: the role of adipocytokines
- Longitudinal measures of circulating leptin and ghrelin concentrations are associated with the growth of young Peruvian children but are not affected by zinc supplementation
- Reference chart for relative weight change to detect hypernatraemic dehydration
- Developmental changes in leptin as a measure of energy status in human infants in a natural ecologic setting
- Neonatal weight loss in breast and formula fed infants
- Postnatal changes in concentrations of free and bound leptin
- Leptin and metabolic hormones in infants of diabetic mothers
- Leptin and metabolic hormones in preterm newborns
- Serum leptin concentrations in infants: effects of diet, sex, and adiposity
- Genetic and Environmental Influences on Human Cord Blood Leptin Concentration