Immaturity or starvation? Longitudinal study of leptin levels in premature infants.

OBJECTIVE: Leptin, the protein product of the ob gene, is a potential placental growth factor and is integral to the body's system of energy regulation as shown in animal models. Premature infants are especially vulnerable to changes in energy regulation, and several studies have demonstrated a rapid fall in leptin values at birth. The purpose of the present investigation was to measure leptin levels in premature infants throughout hospitalization. METHODS: Eligible infants were less than 32 weeks' gestation, appropriate for gestational age, and hospitalized at Christiana Hospital Special Care Nursery. Serum samples for leptin analysis were drawn within 24 h of birth and twice a week thereafter until discharge. Concurrent growth measurements were obtained with each leptin sample. Body mass index, ponderal index, and midarm circumference/head circumference ratios were calculated to assess growth. RESULTS: Leptin levels were low and remained low for the duration of the premature infants' hospitalization (mean +/- SD = 1.35 +/- 0.63 ng/ml/ml, range 0-3.06). After controlling for weight, there was a small (r(2) = 0.1, p < 0.00001) but significant correlation between leptin and postnatal age after 4 days of age. Despite an increase in caloric intake during the study period, there was no relationship between leptin and caloric intake. There were significant negative correlations between measurements of growth and both leptin and the leptin/weight ratio. Maternal diabetes and the use of steroids had small but significant effects on the leptin/weight ratio. CONCLUSION: In this population of predominantly female premature infants, leptin levels were very low as compared to term infants, children and adults, and did not change appreciably over the study period. The low leptin levels seen in these premature infants are similar to those levels seen in malnourished adults, anorexics, and in animal models of starvation. We speculate that a critical adipose store needs to be reached before increased amounts of leptin can be adequately produced. Persistently low leptin levels may also reflect an immaturity in the hypothalamic-pituitary-adrenal axis.

Effect of obesity on estradiol level, and its relationship to leptin, bone maturation, and bone mineral density in children.

The purpose of this study was to investigate 24-h estradiol and leptin levels in obese and nonobese children to further understand the roles of estradiol and leptin in obesity and puberty. We measured serum estradiol, leptin, insulin, glucose, and GH levels every hour for 24 h in 18 obese (12 females and 6 males) and 30 nonobese (11 females and 19 males) prepubertal and early pubertal (stages 1-2) children. Bone age and dual energy x-ray absortiometry (DEXA) were obtained upon completion of the 24-h study. Obese children were significantly younger than nonobese children, with no difference in pubertal stage, height, or bone age between the 2 groups. Obese children had greater bone age to chronological age ratios than nonobese children, indicating a more advanced rate of bone maturation. Mean 24-h estradiol levels correlated significantly with chronological age and bone age as well as with insulin-like growth factor I, insulin-like growth factor-binding protein-3, dehydroepiandrosterone sulfate, mean 24-h GH, and lean body mass. Mean 24-h estradiol levels did not differ between obese and nonobese children [1.65+/-1.47 us. 2.75+/-3.30 pmol/L (0.45+/-0.40 vs. 0.75+/-0.90 pg/mL), respectively]. Similar mean 24-h estradiol levels in obese and nonobese children are consistent with the increased bone maturation of the obese children. Estradiol did not correlate significantly with DEXA fat mass, body mass index, or arm fat measures of adiposity. Obese children had higher 24-h mean leptin concentrations than nonobese children (28.6+/-17.4 vs. 6.8+/-7.1 ng/mL; P < 0.001). Leptin concentrations positively correlated with DEXA fat mass, body mass index, and arm fat measurement of adiposity. Girls had higher 24-h mean leptin levels than boys when controlling for adiposity. Estradiol and leptin concentrations fluctuated over a 24-h period in both groups, with all children having higher leptin concentrations at night and higher estradiol concentrations in the morning. This diurnal rhythm was of a similar pattern, but at higher levels for leptin and lower levels for estradiol in the obese children compared to nonobese children. There was no significant correlation between estradiol and leptin levels. Bone mineral density, as measured by DEXA, did not differ between obese and nonobese children. Similar bone mineral density values in obese and nonobese children are consistent with the increased bone maturation of the obese children. Bone mineral density was not correlated with estradiol or leptin level in these children. In conclusion, obese children had similar estradiol levels and equivalent bone ages at a younger chronological age than nonobese children. Leptin was higher in these obese children, but did not correlate with estradiol level or bone age. These findings suggest that the role of leptin in both obesity and pubertal development is not directly correlated with the estradiol level.

Leptin expression in human mammary epithelial cells and breast milk.

Leptin has recently been shown to be produced by the human placenta and potentially plays a role in fetal and neonatal growth. Many functions of the placenta are replaced by the mammary gland in terms of providing critical growth factors for the newborn. In this study, we show that leptin is produced by human mammary epithelial cells as revealed by RT/PCR analysis of total RNA from mammary gland and immunohistochemical staining of breast tissue, cultured mammary epithelial cells, and secretory epithelial cells present in human milk. We also verify that immunoreactive leptin is present in whole milk at 30- to 150-fold higher concentrations than skim milk. We propose that leptin is secreted by mammary epithelial cells in milk fat globules, which partition into the lipid portion of breast milk.

Placental leptin: an important new growth factor in intrauterine and neonatal development?

BACKGROUND: Leptin, the protein product of the ob gene, is produced by the adipocyte and seems to function as a link between adiposity, satiety, and activity. Leptin has also been found to be necessary for pubertal development, conception, and pregnancy in mice, and is increased in prepubertal children, independent of adiposity, suggesting a role in childhood growth and development. This study investigated 100 mother/newborn pairs to determine the role of leptin in neonatal development. Placental tissue was assayed for leptin mRNA to evaluate it as a source of leptin production in utero. METHODS: One hundred mother/newborn pairs were enrolled in this study. Radioimmunoassay was performed for leptin on maternal venous and newborn cord blood. Leptin concentrations were measured in 43 children in Tanner stages 1 and 2 as a control group. Placental tissue was obtained from five mothers and assayed for leptin mRNA by reverse transcription/polymerase chain reaction (RT/PCR). Human placental cell lines JAR and JEG-3 were also assayed for leptin mRNA expression. RESULTS: Leptin was present in all newborns studied at a mean concentration of 8.8 ng/mL (+/-9.6 standard deviations). Leptin concentrations in cord blood correlated with newborn weight (r = .51), body mass index (BMI) (r = .48), and arm fat (r = .42). There was no correlation between leptin and insulin. When statistically covarying for adiposity for newborns and Tanner stages 1 and 2 children, newborns had greater concentrations of leptin (mean, 10.57 ng/mL) than children (mean, 3.04 ng/mL). Leptin was present in all mothers at a mean value of 28.8 ng/mL (+/-22.2 standard deviations). Leptin concentration correlated with prepregnancy BMI (r = .56), BMI at time of delivery (r = .74), and arm fat (r = .73). Maternal leptin correlated with serum insulin (r = .49). There was no correlation between maternal and newborn leptin concentrations. Thirteen percent of newborns had higher leptin concentrations than their mothers. Placental tissue from five separate placentas expressed leptin mRNA at comparable or greater levels than adipose tissue. Two human trophoblastic placental cell lines, JAR and JEG-3, also expressed leptin mRNA. CONCLUSIONS: The correlation between leptin and adiposity found in children and adults was also found in newborns. Serum leptin concentrations in newborns were increased more than three-fold compared with children in Tanner stages 1 and 2 when controlling for adiposity, suggesting that leptin concentrations in the newborn are not explained by adiposity alone. Maternal leptin concentrations correlated with measures of adiposity at delivery but did not correlate with newborn adiposity or leptin. Leptin mRNA was expressed both in placental tissue and in two human placental cell lines. These data suggest that leptin has a role in intrauterine and neonatal development and that the placenta provides a source of leptin for the growing fetus.

Serum leptin in children with obesity: relationship to gender and development.

BACKGROUND: The identification of the ob gene and its adipocyte-specific protein leptin has provided the first physiologic links to the regulatory system controlling body weight. In adults, elevations of serum leptin concentrations were closely correlated with the percentage of body fat. This study investigated whether leptin concentrations were elevated in obese children and the relationship between leptin concentrations and gender, pubertal stage, and race. METHODS: Seventy-seven children (44 girls and 33 boys), mean age, 11.3 years, with a body mass indices (BMIs) greater than 95% for age, race, and gender (mean BMI, 34.4) constituted the obese group. Thirty children (20 girls and 10 boys), mean age, 13.3 years, with BMIs less than 85% for age, race, and sex formed the control group. Radioimmunoassay for serum leptin was performed on a blood sample collected from each child after an overnight fast. RESULTS: The mean serum concentration of leptin in the obese group was 38.6 (SD, 21) ng/mL compared with 7.8 (SD, 6.5) ng/mL in the control group. Serum leptin concentrations were highly correlated with BMI (r = .88). Analysis of covariance revealed a main effect for Tanner stage and gender. CONCLUSIONS: As in adults, obese children have high concentrations of serum leptin, which were highly correlated with arm fat and BMI. Increased adipose tissue in children is associated directly with serum leptin concentration. Leptin concentrations were found to vary with Tanner stage independent of adiposity. Compared with boys, girls had increased leptin concentrations independent of adiposity. It was hypothesized that children manifest a relative "leptin resistance" to support increased growth and development of reproductive capacity.