Reduced placental perfusion causes an increase in maternal serum leptin

OBJECTIVE: We tested the hypothesis that the inadequately perfused placenta increases production of leptin, which can be detected in maternal serum. STUDY DESIGN: Sprague-Dawley rats (n=13), on day 14 of gestation, had placement of clips on the aorta and the ovarian arteries providing 35 per cent occlusion of the vessels. Eight rats had sham surgery and 14 rats served as non-surgical controls. All animals were sacrificed on day 19 of gestation. Maternal serum was obtained, and pups and placentae were weighed. RESULTS: Both placental weights and pup weights were reduced due to reduced uterine perfusion and were negatively correlated with maternal serum leptin (P=0.018 and 0.028, respectively). Maternal serum leptin was increased in the treatment group (2.21 ng/ml+/-64 ng/ml) compared to controls (1.66 ng/ml+/-38 ng/ml) (P=0.031). CONCLUSIONS: Our findings suggest that reduced placental perfusion results in an increase in maternal serum leptin. Further investigation is needed to determine if maternal serum leptin may be useful in identifying pregnancies with uteroplacental insufficiency.     

妊娠期糖尿病母儿血清瘦素水平和胎盘瘦素表达及其与胰岛素的关系

目的 :探讨妊娠期糖尿病母儿瘦素水平变化和胎盘瘦素mRNA表达 ,以及与胰岛素的关系。方法 :1999年 10月至 2 0 0 2年 2月 ,采用放射免疫法检测 18例妊娠期糖尿病孕妇 (观察组 )、2 0例正常孕妇 (对照组 )母儿血胰岛素和瘦素水平。采用逆转录聚合酶链反应 (RT PCR)和荧光定量分析法检测胎盘瘦素mRNA表达水平。结果 :观察组母血胰岛素、母血瘦素、脐血胰岛素、脐血瘦素和胎盘组织mRNA表达水平高于对照组 (P <0 .0 5 ) ,观察组母血瘦素与母血胰岛素水平与新生儿体重正相关 (r =0 .5 0 ,0 .4 8;P <0 .0 5 ) ,脐血瘦素和胰岛素水平与胎盘瘦素mRNA表达水平正相关 (r =0 .5 1,0 .5 3;P <0 .0 5 )。结论 :妊娠期糖尿病母儿同时存在高瘦素血症和高胰岛素血症 ,高胰岛素血症上调胎盘组织瘦素mRNA的表达 ,与巨大儿发生有关。     

Hormonal regulation of neonatal weight: placental leptin and leptin receptors

Objective To examine whether umbilical and maternal leptin levels correlate with birthweight, placental weight, and maternal weight; and to detect membrane-bound leptin receptors in placental tissue as well as soluble leptin receptors in umbilical and maternal blood.
Design Prospective observational study.
Setting University teaching hospital.
Methods Serum levels of leptin and soluble leptin receptors were analysed in 31 randomly selected mother/newborn pairs at delivery. In addition, placental tissue was assayed for leptin receptors using immunocytochemistry and Western blot.
Results The mean [SD] leptin level in umbilical cord venous blood (7.1 ng/mL [4.0]) was significantly lower (   P < 0.001  ) than in maternal blood (22.5 ng/mL [10.8]). Umbilical cord leptin concentrations correlated significantly with birthweight (   P < 0.001  ), placental weight (   P < 0.005  ) but not with maternal leptin. Maternal leptin concentrations correlated only with maternal weight (   P < 0.001  ). In chorionic villous tissue, trophoblasts stained strongly positive for leptin receptor-like immunoreactivity. Two membrane-bound isoforms of the leptin receptor were also detected in placental tissue. In both umbilical and maternal serum, a soluble leptin receptor was found migrating as broad band at M_r 97,000 D.
Conclusion The present data strongly reinforce the idea that circulating leptin levels may provide a growth-promoting signal for fetal development during late pregnancy. While membrane-bound leptin receptors may be involved in autocrine regulation of placental leptin production, the soluble receptor form may serve as a transport vehicle for leptin to fetal tissues.     

Maternal serum and umbilical cord blood leptin concentrations with fetal growth restriction

OBJECTIVE: To ascertain whether fetal growth restriction is associated with alterations of leptin concentrations in umbilical cord blood and maternal serum. METHODS: Maternal serum and umbilical cord blood leptin concentrations were determined by immunoradiometric assay at term in 43 women with uncomplicated singleton pregnancies (group A) and in 27 women with singleton pregnancies complicated by fetal growth restriction (group B), all with normal pregravid body mass index (BMI). RESULTS: Maternal serum leptin concentrations were significantly higher in group B compared with group A (45.0 ng/mL [range 34.2-54.9] versus 29.0 ng/mL [range 24.7-33.3]; P<.01). Umbilical cord blood leptin levels were significantly lower in group B compared with group A (8.4 ng/mL [range 3.6-13.2] versus 13.1 ng/mL [9.7-16.5]; P<.01). Maternal serum leptin levels were not significantly correlated with maternal BMI or with neonatal birth weight in either group. Umbilical cord blood leptin concentrations were significantly correlated with neonatal birth weight in both groups. CONCLUSION: Growth restricted fetuses at term show umbilical cord blood leptin concentrations significantly lower than those in normal fetuses, suggesting that fetal adipose tissue is a major source of leptin. Maternal serum leptin concentrations are higher in the presence of a growth restricted fetus. This increase might be due to an intrinsic placental mechanism, by which small placentas produce more leptin as a compensatory mechanism, or to early hypoxia.     

Maternal serum leptin concentrations do not correlate with cord blood leptin concentrations in normal pregnancy

OBJECTIVE: To determine whether there is a difference in maternal leptin concentration and cord blood concentration, consistent with the hypothesis of a noncommunicating, two-compartement model of fetoplacental leptin regulation. METHODS: Blood samples were collected from 139 women, identified as having an uncomplicated pregnancy, from an antecubital vein at delivery. Cord blood samples were taken from the umbilical vein. Leptin was measured by radioimmunoassay, and its relationship to fetal and maternal anthropometrics was assessed by Spearman correlation. Differences in maternal and cord blood leptin levels between male and female infants were tested with the Mann-Whitney Utest. Maternal and cord blood leptin were compared by the Wilcoxon signed rank test. The outcome measures were maternal and cord blood leptin at delivery, fetal birth weight, length, weight/length ratio, and ponderal index, maternal prepregnancy body mass index, pregnancy weight gain, relative weight gain, and body mass index at delivery. RESULTS: No correlations were found between maternal and cord blood leptin concentrations. Fetal leptin level correlated with birth weight (rho = 0.665; P <.0001), length (rho = 0.490; P <.0001), ponderal index (rho = 0.260; P =.002), and weight/length ratio (rho = 0.625; P <.0001). Median leptin concentrations were higher in female (9.3 ng/mL, range 1.5-34.4 ng/mL) than in male (8.2 ng/mL, range 1.6-38.3 ng/mL) neonates, but this difference was statistically not significant. Logistic regression analysis showed a significant influence on umbilical venous leptin concentration for birth weight (P <.0001) but not for gender. Maternal leptin concentrations were significantly higher than cord leptin concentrations (P <.0005 for the male and female neonates and the entire group). CONCLUSION: There was no correlation between maternal and cord leptin, which supports the hypothesis of a noncommunicating, two-compartment model of fetoplacental leptin regulation.     

Leptin concentrations in maternal serum and cord blood: relationship to maternal anthropometry and fetal growth.

OBJECTIVE: To determine 1. the relationship between maternal serum leptin concentrations and maternal anthropometry and 2. the relationship between cord serum leptin concentrations at birth and neonatal anthropometry. DESIGN: Prospective cohort study of fetal growth in low-risk pregnancies. SETTING: University teaching hospital. SAMPLE: Thirty-nine women and their babies taking part in a fetal growth study. METHODS: Blood was taken from the women between 10-20 weeks of gestation and from the umbilical cord of their babies at delivery. Serum leptin was measured by radio-immunoassay. Maternal anthropometric measurements were recorded at booking. Neonatal anthropometric measurements were recorded within 48 hours after delivery. Linear regression analysis was used to explore the relationship between serum leptin concentrations and anthropometric measures and multiple regression analysis then applied to determine which variables remained independently associated with leptin. RESULTS: The median (range) leptin concentration in maternal serum was 11.8 ng/mL (1.7-39.7) and in cord blood was 4.2 ng/mL (0.6-21.4). Maternal leptin levels correlated with maternal weight, body mass index, midarm circumference and skinfold thickness, but not with birthweight, placental weight or maternal height. Body mass index and midarm circumference remained significant after multiple regression analysis. Cord leptin levels correlated with birthweight, birthlength, placental weight and skinfold thickness but not with ponderal index. Birthweight and subscapular skinfold thickness remained significant after multiple regression analysis. Cord leptin concentrations did not correlate with maternal leptin concentrations. CONCLUSIONS: We suggest that there are very strong associations between maternal leptin and maternal adiposity in pregnancy, and between cord leptin at delivery and birthweight, as well as other anthropometric markers of fetal growth.     

Placental leptin and pregnancy pathologies

Leptin, the protein encoded by the Ob gene, is produced by the white adipose tissue and by the placenta during pregnancy. Placental leptin production makes a substantial contribution to maternal circulating levels during pregnancy which rapidly decrease and return to normal after delivery. Leptin has been detected in fetal plasma as early as week 18 of gestation, and umbilical leptin concentrations are closely related to birth weight. This has led to the hypothesis that fetal fat mass mainly determines fetal circulating leptin. Placental leptin production is increased in choriocarcinoma, preeclampsia and type 1 diabetes. Estrogens, hypoxia and insulin have been suggested as positive regulators of placental leptin production. Maternal leptinemia might act as a sensor of energy balance during pregnancy. The presence of both leptin and leptin receptors in the placenta suggests that leptin can act by autocrine or endocrine pathways in the human placenta. The roles of fetal leptin and consequences of increased placental leptin production in pathological pregnancies have yet to be elucidated.     

Placental leptin

Placental tissues from humans, rodents and farm animals contain leptin and its receptor. Leptin produced by the human placenta has the same size, charge and immunoreactivity as leptin produced by adipose tissue. However, the expression of human placental leptin appears to be regulated by a placenta-specific upstream enhancer. In this review the occurrence of leptin and its receptor in a range of species and placental types is described, and its significance during pregnancy discussed. Placental leptin contributes to the increase in maternal circulating concentrations of leptin during late pregnancy when it is likely to have an endocrine role in regulating maternal energy balance. Placental leptin may have angiogenic and immunomodulatory activities, which affect the placenta in an autocrine or paracrine manner. It also appears to affect fetal growth and development by binding to leptin receptors present in fetal organs.     

Endothelin and the regulation of uterine and placental perfusion in hypoxia-induced fetal growth restriction

OBJECTIVE: Normal placental function is dependent on maintenance of uteroplacental perfusion. Endothelin, a potent vasoconstrictor, is produced in and is active in the uteroplacental vasculature. The purpose of this study was to determine the role of endothelin in the regulation of uteroplacental perfusion under normal conditions, and in hypoxia-induced fetal growth restriction. METHODS: Timed-pregnant Sprague-Dawley rats, outfitted with arterial catheters, were maintained in either a normoxic or a normobaric hypoxic (12% oxygen) atmosphere from day 18 to 21 of gestation. During this time, the endothelin receptor A antagonist, A-127722, or its vehicle was administered. Regional blood flow was determined on gestational day 21 using 57Co-labeled microspheres. Data were analyzed by analysis of variance with statistical significance accepted at P<.05. RESULTS: Both placental and uterine placental bed perfusion were significantly decreased by hypoxia and returned to normal values with the endothelin antagonist (P<.01 and P<.05, respectively). Fetal weights were significantly lower in the hypoxic group (P<.001) and restored to control levels by the antagonist. CONCLUSION: In the rat, endothelin contributes little to the regulation of uteroplacental perfusion under normal conditions. Hypoxia results in a decrease in perfusion of the uteroplacental bed and of the placenta, and perfusion in both of these beds is normalized by endothelin A receptor antagonism. We conclude that endothelin plays a primary role in the pathophysiology of hypoxia-induced fetal growth restriction by reducing uteroplacental perfusion.     

Role of Leptin in Pregnancy—A Review

Leptin is an adipocyte-derived hormone that decreases food intake and body weight via its receptor in the hypothalamus. In rodents, it also modulates glucose metabolism by increasing insulin sensitivity. We previously reported that leptin is produced by human placental trophoblasts. We also revealed that leptin gene expression in the placenta was augmented in severe pre-eclampsia, and suggested that placental hypoxia may play a role in this augmentation. Maternal plasma leptin levels correlated well with mean blood pressure, but not with body mass index. Plasma leptin levels in pre-eclamptic women with IUGR were higher than those without IUGR (P< 0.05).We further examined the effects of hyperleptinemia on the course of pregnancy by using transgenic mice (Tg) overexpressing leptin. In pregnant Tg mice, food intake was significantly less than non-Tg, and the fetal body weights were reduced to approximately 70 per cent of those of non-Tg.Resistin is a novel adipocyte–derived hormone that decreases insulin sensitivity and increases plasma glucose concentration, thus contributing the development of obesity-related type II diabetes mellitus. We recently found that resistin gene is expressed in the human placenta as well as adipose tissue. In this review, possible roles of placental leptin and resistin are discussed.     

Placental miR-1301 is dysregulated in early-onset preeclampsia and inversely correlated with maternal circulating leptin

Introduction

miRNAs are small non-coding RNAs important for the regulation of mRNA in many organs including placenta. Adipokines and specifically leptin are known to be dysregulated in preeclampsia, but little is known regarding their regulation by miRNAs during pregnancy.

Methods

We performed high-throughput sequencing of small RNAs in placenta from 72 well-defined patients: 23 early-onset preeclampsia (PE), 26 late-onset PE and 23 controls. The regulation of some miRNAs was confirmed on qRT-PCR. Maternal circulating levels and placental mRNA of leptin, resistin and adiponectin were measured using Bio-Plex and qRT-PCR.

Results

We found that miR-1301, miR-223 and miR-224 expression was downregulated in early-onset PE, but not in late-onset PE, compared to controls. In silico analysis predicted the leptin gene (LEP) to be a target for all three miRNAs. Indeed, we found significant correlation between maternal circulating levels of leptin and placental LEP expression. In addition, we found a significant inverse correlation between maternal circulating leptin/placental LEP expression and placental miR-1301 expression levels. Interestingly, placental expression of miR-1301 was also correlated with newborn weight percentile and inversely correlated with both maternal systolic and diastolic blood pressure prior to delivery.

Discussion

Our results confirm that placenta is a major site of LEP expression during pregnancy. It further suggests that miR-1301 could be involved in the regulation of leptin during pregnancy and may play a role in early-onset PE.

Conclusions

miR-1301 is dysregulated in early-onset preeclampsia and could possibly play a role in the regulation of leptin during pregnancy.     

Maternal growth restriction and stress exposure in rats differentially alters expression of components of the placental glucocorticoid barrier and nutrient transporters

The placenta plays a major role in the development of fetal growth restriction, which affects 10% of pregnancies and contributes to chronic adult disease risk. We have reported that female rats born small develop cardiometabolic dysfunction only during pregnancy. The physiological tests performed during pregnancy induced a maternal stress response as indicated by increased maternal corticosterone concentrations. This stress effected placental growth compared to females who were unhandled during pregnancy. Maternal stress and growth restriction independently program F2 offspring metabolic dysfunction. This study investigated the effects of maternal stress and growth restriction on placental and fetal metabolic parameters that may contribute to F2 offspring metabolic disease. Maternal growth restriction reduced F2 fetal weight whilst maternal stress reduced placental weight. Stressed mothers had reduced insulin and increased glucose concentrations, changes that were reflected in the fetus. Fetal β-cell number was reduced by maternal growth restriction, but was increased by stress exposure. Maternal growth restriction reduced placental Slc2a1, Igf2, Slc38a2 and Nr3c1 gene expression. Maternal stress decreased the expression of Slc2a1, Igf2, Slc38a2, Nr3c1, Slc2a3, Slc2a4, Nr3c2, Hsd11b2, Crhr1 and Ogt. Maternal birth weight effects on fetal weight were likely due to changes in placental nutrient transporter and Igf2 expression. On the contrary, maternal stress induced a systemic effect by altering maternal metabolic parameters, placental gene expression and fetal glucose and insulin concentrations. This study highlights the importance of informing pregnant women on effective ways to cope with stress during pregnancy to prevent adverse long-term disease outcomes in their children.     

Cardiac output and uteroplacental blood flow in diet-restricted and diet-repleted pregnant rats

Cardiac output and uteroplacental blood flow were measured with 15 mu radioactive microspheres in anesthetized pregnant rats which were fed: (1) ad libitum throughout gestation; (2) a 50% restricted diet from day 5 of gestation; and (3) a 50% restricted diet from days 5 to 13 of gestation and ad libitum from day 14 of gestation. An additional group of nonpregnant rats fed ad libitum was also used. Dietary restriction caused a net maternal weight loss and a 20% reduction in mean fetal weight and mean placental weight by day 21 of gestation. Restricted dams fed ad libitum during the last week of gestation showed a net maternal weight gain, while mean fetal weight, but not placental weight, was near that of the ad libitum--fed controls. In the diet-restricted rats, total cardiac output was reduced 30% relative to controls by days 20 and 21 of gestation, but cardiac output per unit maternal body weight was not significantly different. Dietary restriction decreased both total uterine and placental blood flow by about 65%. Diet repletion late in gestation did not significantly increase total cardiac output or cardiac output per unit body weight. Total uterine and placental blood flows were near those of controls, primarily because of an increased fraction of cardiac output distributed to the uterus.     

Decreased maternal serum leptin in pregnancies complicated by preeclampsia

OBJECTIVE: To determine whether circulating levels of leptin differed between women with preeclampsia and women who had an uncomplicated pregnancy. METHODS: Maternal and umbilical venous plasma leptin concentrations obtained at delivery were compared in 36 pairs of women with either preeclampsia or normal pregnancy, matched 1:1 for prepregnancy body mass index and fetal gestational age at delivery. RESULTS: Prepregnancy body mass index was 21.1 +/- 2.1 kg/m2 in either study group (range 17.6-25.3 kg/m2 and 17.7-25.3 kg/m2 in the normal and preeclamptic group, respectively). Mean fetal gestational age at delivery was 40.1 +/- 1.3 weeks and 40.1 +/- 1.2 weeks in the normal and preeclamptic group, respectively. Median leptin concentrations were significantly lower (P <.0001) in women with preeclampsia (8.3 ng/mL, range 3.5-20.0 ng/mL) than in normal pregnant women (20.2 ng/mL, range 6.0-63.7 ng/mL). Median umbilical venous leptin was not significantly different between groups (preeclampsia 11.8 ng/mL, range 2.0-37.2 ng/mL; normal 7.6 ng/mL, range 1.6-24.3 ng/mL; P = .377). Umbilical venous leptin levels correlated positively with birth weight in both groups (preeclampsia rho = 0.501, P = .002; normal rho = 0.517, P = .001), whereas no correlations were found between maternal and fetal hormone concentrations. Maternal leptin concentrations did not correlate with birth weight. CONCLUSION: Our data suggest that the correlation between umbilical venous leptin concentration and birth weight is independent of the presence of preeclampsia. Given the inconsistency in literature concerning circulating leptin levels in preeclampsia, further studies should investigate the regulatory systems of leptin in preeclampsia.     

Effect of morphine on the reduced uteroplacental perfusion model of pre-eclampsia in rats

Objectives

To investigate the effect of morphine on the reduced uteroplacental perfusion pressure (RUPP) model of pre-eclampsia in rats.

Study design

The abdominal aorta and ovarian arteries of pregnant rats were isolated and clipped on gestational day 14. The chronic morphine treatment group received naltrexone 5 mg/kg 1 h before each dose of morphine. L-nitromonomethylarginine 2 mg/kg was administrated in the same pattern. The control group received saline 10 ml/kg. Systolic blood pressure, blood urea nitrogen (BUN), creatinine, creatinine clearance, urinary protein, urinary nitrite/nitrate excretion, and fetal and placental weights were determined.

Results

Morphine significantly reduced systolic blood pressure, fetal and placental weights, plasma BUN, creatinine and urinary protein in RUPP rats compared with control rats. Urinary nitrite/nitrate excretion and creatinine clearance were significantly increased in response to morphine treatment.

Conclusion

Morphine reduced blood pressure and improved renal function in the RUPP model of pre-eclampsia, but this was associated with reduced fetal and placental weights.     

Effect of long-term administration of beta 2-sympathomimetic drug in the diet-restricted pregnant rat model

To assess whether the maternal-fetal balance could be altered in favor of the fetus during malnutrition by increasing uteroplacental blood flow, 0.5 mg of hexoprenaline per day was added to the diet of one group of diet-restricted rats, while another group served as controls. The radionuclide-labeled microsphere method was used to determine blood flow to the maternal placentas and other organs. Maternal carcass weight but not fetal or placental weights were increased in the hexoprenaline-fed rats. Blood flow to the ileum, jejunum, hepatic artery, kidneys, and placentas was significantly greater in the hexoprenaline group compared with those rats fed the restricted diet alone. Although the placental blood flow was increased in the hexoprenaline-fed rats, the supply of nutrients remained restricted, and in the mother the inherent maternal-fetal balance was maintained by an increase in the blood flow to the liver and small intestine.     

Leptin and gestational weight gain: relation of maternal and cord blood leptin to birth weight

OBJECTIVES: To determine maternal serum leptin concentrations throughout normal pregnancy, as well as cord blood leptin concentration, and to correlate serum and cord blood leptin levels with gestational weight gain and birth weight, respectively. METHODS: This study comprised 52 normal pregnant women, including 11 in the first, 19 in the second, and 22 in the third trimester, in addition to 30 healthy, fertile nonpregnant women of comparable age and with normal body mass index (BMI). Maternal blood and fetal cord blood samples were withdrawn from the normal, healthy pregnant women and the nonpregnant controls for the determination of serum leptin by a specific radioimmunoassay. RESULTS: Maternal serum leptin concentrations in the first trimester did not differ significantly from those of healthy nonpregnant control subjects, whereas leptin concentrations in the second and third trimesters were elevated significantly. There were significant positive correlations between maternal serum leptin concentration and gestational age, gestational weight, and BMI. Cord blood leptin concentration correlated positively with birth weight and third trimester maternal serum leptin. CONCLUSION: Elevated serum leptin is associated with maternal adiposity and risk of developing large for gestational age infants.     

The influence of leptin on placental and fetal volume measured by three-dimensional ultrasound in the second trimester

For a couple of years mechanisms influencing placental and fetal growth and the functioning of leptin, the protein product of the ob/ob gene, have been subjects of intensive research. This study's aim was to investigate whether maternal serum leptin and amniotic fluid leptin have an influence on placental and fetal size measured by three-dimensional ultrasound in the second trimester. To determine this, 40 women with a singleton intrauterine pregnancy at the time of the amniocentesis were included in the study. Placental and fetal volume measurements were obtained and correlated to maternal serum leptin, amniotic fluid leptin, body mass index and gestational age. Multiple regression analysis identified amniotic fluid leptin as an independent negative predictor of placental and fetal volume (r = -2.29, p = 0.032 and r = -0.95, p = 0.011, respectively). In contrast, there was no correlation between maternal serum leptin and placental or fetal volume. The median leptin level in amniotic fluid (9.5 ng/ml) was significantly lower than in maternal blood (18.6 ng/ml). However, there was no significant correlation between maternal serum leptin and amniotic fluid leptin (r = 0.208, n.s.). Body mass index did not reveal any significant influences on placental or fetal volume. The relatively high level of amniotic fluid leptin and its inverse correlation on placental and fetal volume in the second trimester suggest that it possibly plays a role as an anti-placental growth hormone or feedback modulator of substrate supply to the fetus and placenta.