Fetal Plasma Leptin Concentrations Research Articles

Placental Amino Acid Transport and Placental Leptin Resistance in Pregnancies Complicated by Maternal Obesity

Hypothesis and study objectives We hypothesized that maternal obesity is associated with increased placental amino acid transport and hyperleptinemia. Our objectives were to study placental amino acid transport and the effect of leptin on placental amino acid transport in vitro in the setting of maternal obesity. Materials and methods Seven lean, BMI at entry 22.4, and seven obese, BMI at entry 31.5 ( p < 0.001), pregnant women were studied at 39 weeks. We measured baseline and leptin-stimulated placental system A sodium-dependent neutral amino acid transporter (SNAT) activity, placental immunoreactive protein expression of SNAT, leptin and leptin receptor, and maternal and fetal plasma leptin concentrations, with significance set at p ≤ 0.05. The primary outcome measure was placental SNAT activity. Results The obese group had decreased placental SNAT activity ( p = 0.005), maternal hyperleptinemia ( p = 0.01) and decreased syncytiotrophoblast expression of leptin receptor ( p = 0.01) and SNAT-4 ( p < 0.001). Placental amino acid uptake was significantly stimulated by leptin in the lean group as compared to the obese group. Maternal weight gain and offspring birth weights were not different between groups. Conclusion Maternal obesity was accompanied by decreased placental SNAT activity associated with maternal hyperleptinemia and placental leptin resistance in spite of appropriate maternal weight gain and normally grown neonates. These findings suggest altered placental function that may have clinical implications in obese pregnant women.

A Study to Determine if Acute Maternal and Fetal Hyperglycemia/Insulinemia Induces Leptin Production during Pregnancy

In pregnant primates, the effect of post-prandial hyperglycemic or insulinemic states on leptin production is not known. Our goal was to conduct a controlled study using an established pregnant baboon model ( PAPIO ANUBIS) to determine whether acute glucose changes would have an effect on maternal or fetal plasma leptin levels. Two animals were operated on at 138 and 140 days of gestation (term approximately 184 days) by placing 4 cannulae in the maternal aorta, inferior vena cava, fetal carotid artery, and the amniotic cavity. At 145 and 150 days, glucose infusions were started via the maternal femoral vein. Animal 1 received 7.5 gm of glucose over a 2-hour period at 145 th day. Animal 2 received 20 gm of glucose over a 1-hour period at 150th day. Both animals remained ad libitum throughout the experiments. Maternal and fetal blood samples were obtained from the arterial lines before the glucose infusion and at half hour intervals to include 30 minutes post-infusion. Significant changes from baseline concentrations were observed for maternal and fetal glucose and insulin concentrations in response to both glucose challenges. Maternal and fetal plasma leptin concentrations did not correlate with glucose or insulin changes. This preliminary study demonstrated that in primates, acute changes in circulating maternal or fetal glucose or insulin concentration do not affect maternal or fetal plasma leptin concentrations. These results suggest that alterations in leptin secretion by the maternal-placental-fetal unit may only occur in pathological states.

Late but Not Early Gestational Maternal Growth Hormone Treatment Increases Fetal Adiposity in Overnourished Adolescent Sheep

In the overnourished adolescent sheep, maternal tissue synthesis is promoted at the expense of placental growth and leads to a major decrease in lamb birth weight at term. Maternal growth hormone (GH) concentrations are attenuated in these pregnancies, and it was recently demonstrated that exogenous GH administration throughout the period of placental proliferation stimulates uteroplacental and fetal development by Day 81 of gestation. The present study aimed to determine whether these effects persist to term and to establish whether GH affects fetal growth and body composition by increasing placental size or by altering maternal metabolism. Adolescent recipient ewes were implanted with singleton embryos on Day 4 postestrus. Three groups of ewes offered a high dietary intake were injected twice daily with recombinant bovine GH from Days 35 to 65 of gestation (high intake plus early GH) or from Days 95 to 125 of gestation (high intake plus late GH) or remained untreated (high intake only). A fourth moderate-intake group acted as optimally nourished controls. Pregnancies were terminated at Day 130 of gestation (6 per group) or were allowed to progress to term (8-10 per group). GH administration elevated maternal plasma concentrations of GH, insulin, glucose, and nonesterified fatty acids during the defined treatment windows, while urea concentrations were decreased. At Day 130, GH treatment had reduced the maternal adiposity score, percentage of fat in the carcass, and internal fat depots and leptin concentrations, predominantly in the high-intake plus late GH group. Placental weight was lower in high-intake vs. control dams but independent of GH treatment. In contrast, fetal weight was elevated by late GH treatment, and these fetuses had higher relative carcass fat content, perirenal fat mass, and liver glycogen concentrations than all other groups. Expression of leptin mRNA in fetal perirenal fat and fetal plasma leptin concentrations were not significantly altered by maternal nutritional intake or GH. In pregnancies proceeding to term, the duration of gestation, fetal placental mass, and lamb birth weight were reduced in high-intake compared with control dams but were not significantly affected by GH treatment. In conclusion, exogenous GH has profound effects on maternal endocrinology, metabolism, and body composition when administered during early and late pregnancy. Treatment during late pregnancy has a modest effect on fetal growth independent of placental size and a profound effect on fetal adiposity, which may have implications beyond the fetal period.

Prenatal programming of postnatal obesity: fetal nutrition and the regulation of leptin synthesis and secretion before birth.

Exposure to either an increased or decreased level of intrauterine nutrition can result in an increase in adiposity and in circulating leptin concentrations in later life. In animals such as the sheep and pig in which fat is deposited before birth, leptin is synthesised in fetal adipose tissue and is present in the fetal circulation throughout late gestation. In the sheep a moderate increase or decrease in the level of maternal nutrition does not alter fetal plasma leptin concentrations, but there is evidence that chronic fetal hyperglycaemia and hyperinsulinaemia increase fetal fat mass and leptin synthesis within fetal fat depots. Importantly, there is a positive relationship between the relative mass of the 'unilocular' component of fetal perirenal and interscapular adipose tissue and circulating fetal leptin concentrations in the sheep. Thus, as in the neonate and adult, circulating leptin concentrations may be a signal of fat mass in fetal life. There is also evidence that leptin can act to regulate the lipid storage, leptin synthetic capacity and potential thermogenic functions of fat before birth. Thus, leptin may act as a signal of energy supply and have a 'lipostatic' role before birth. Future studies are clearly required to determine whether the intrauterine and early postnatal nutrient environment programme the endocrine feedback loop between adipose tissue and the central and peripheral neuroendocrine systems that regulate energy balance, resulting in an enhanced risk of obesity in adult life.

Impact of periconceptional nutrition on maternal and fetal leptin and fetal adiposity in singleton and twin pregnancies.

It has been proposed that maternal nutrient restriction may alter the functional development of the adipocyte and the synthesis and secretion of the adipocyte-derived hormone, leptin, before birth. We have investigated the effects of restricted periconceptional undernutrition and/or restricted gestational nutrition on fetal plasma leptin concentrations and fetal adiposity in late gestation. There was no effect of either restricted periconceptional or gestational nutrition on maternal or fetal plasma leptin concentrations in singleton or twin pregnancies during late gestation. In ewes carrying twins, but not singletons, maternal plasma leptin concentrations in late gestation were directly related to the change in ewe weight that occurred during the 60 days before mating [maternal leptin = 0.9 (change in ewe weight) + 7.8; r = 0.6, P < 0.05]. In twin, but not singleton, pregnancies, there was also a significant relationship between maternal and fetal leptin concentrations (maternal leptin = 0.5 fetal leptin + 4.2, r = 0.63, P < 0.005). The relative mass of perirenal fat was also significantly increased in twin fetal sheep in the control-restricted group (6.0 +/- 0.5) compared with the other nutritional groups (control-control: 4.1 +/- 0.4; restricted-restricted: 4.4 +/- 0.4; restricted-control: 4.3 +/- 0.3). In conclusion, the impact of maternal undernutrition on maternal plasma leptin concentrations during late gestation is dependent on fetal number. Furthermore, we have found that there is an increased fetal adiposity in the twins of ewes that experienced restricted nutrition throughout gestation, and this may be important in the programming of postnatal adiposity.

Fetal and maternal plasma leptin levels during the second half of normal pregnancies and those with Down syndrome

Objective: To assess the correlation of fetal and maternal plasma leptin concentrations during the second half of uncomplicated, euploid pregnancies and to compare these values with those obtainedfrom pregnancies with Down syndrome.Methods: Paired maternal venous and fetal umbilical blood samples were obtained during cordocentesis in 36 uncomplicated, euploid pregnancies and nine pregnancieswith Down syndrome fetuses. Concentrations of leptin were measured by sensitive radioimmunoassay. Results: Among pregnancies with euploid fetuses, there was significant correlation between both fetal andmaternal leptin levels and gestational age (r = 0.464, p = 0.005 and r = 0.629, p < 0.001, respectively). Fetal plasma leptin concentrations also correlated with maternal levels(r = 0.485, p = 0.003), but fetal levels were significantly lower than maternal values (mean 2.12 ± 0.44 ng/ml vs. 17.79 ± 5.48 ng/ml, respectively; p < 0.001). Downsyndrome fetuses had significantly lower fetal plasma leptin levels than gestational age-matched control euploid fetuses (0.72 + 0.54 ng/ml vs. 2.12 + 0.44 ng/ml; p < 0.002). However, there wasno difference in maternal leptin concentrations between euploid and Down syndrome pregnancies.Conclusion: In euploid pregnancies, fetal leptin levels were significantly lower than the correspondingmaternal values but increased across gestation. Down syndrome was associated with significantly lower fetal leptin levels.

Fetal leptin is a signal of fat mass independent of maternal nutrition in ewes fed at or above maintenance energy requirements.

In adults, circulating leptin concentrations are dependent on body fat content and on current nutritional status. However, the relationships among maternal nutrient intake, fetal adiposity, and circulating leptin concentrations before birth are unknown. We investigated the effects of an increase in nutrient intake in the pregnant ewe on fetal adiposity and plasma leptin concentrations during late gestation. Between 115 and 139-141 days gestation (term = 147 +/- 3 days gestation), ewes were fed a diet calculated to provide either maintenance (control, n = 6) or approximately 155% of maintenance requirements (well-fed, n = 8). The fetal fat depots (perirenal and interscapular) were dissected, and the relative proportion of unilocular and multilocular adipocytes in each depot was determined. Maternal plasma glucose and leptin concentrations were significantly increased in well-fed ewes. Fetal plasma glucose concentrations were also higher in the well-fed group (115-139 days gestation: control, 1.65 +/- 0.14 mmol/L; well-fed, 2.00 +/- 0.14 mmol/L; F = 5.76, P < 0.04). There was no effect of increasing maternal feed intake on total fat mass, the relative mass of unilocular fat, or fetal plasma leptin concentrations (115-139 days gestation: control, 5.2 +/- 0.8 ng/ml; well-fed, 4.7 +/- 0.7 ng/ml). However, in both the control and well-fed groups fetal plasma leptin concentrations (y) were positively correlated with the relative mass of unilocular fat (x): y = 1.51x + 1.70; (R = 0.76, P < 0.01). Thus, fetal leptin may play a role as a signal of unilocular fat mass in the fetus when maternal nutrient intake is at or above maintenance requirements.

Preeclampsia disrupts the normal physiology of leptin.

This study was designed to examine the leptin levels of preeclamptic women and their offspring, to compare them with those of normal pregnant women and to search for a correlation between maternal and fetal plasma leptin levels and their anthropometric characteristics. Twenty-one preeclamptic women and their babies were enrolled into the study. Control group consisted of 21 normal pregnant women and their babies, whose birth weights, gestational ages, and genders match with those of babies born to preeclamptic women. Median maternal leptin concentrations of the preeclamptic group (15.3 ng/mL) were significantly higher ( p = 0.03) than the control group (10.4 ng/mL). However, fetal plasma leptin concentrations were not different ( p = 0.06) between the two groups. Fetal plasma leptin levels were correlated with birth weight, length, body mass index, gestational age, and fetal hematocrit levels in the control group. However, no correlation between leptin levels and these parameters was found in the preeclamptic group. Therefore, preeclampsia may be thought to disrupt normal leptin physiology.

Leptin is a signal of adiposity in fetuses of pregnant ewes fed at or above maintenance energy requirements

In the adult, circulating leptin concentrations are dependent on body fat content and on current nutrient intake. Whilst leptin concentrations in umbilical cord blood correlate with fetal adiposity in the human neonate, it is unknown whether leptin acts as a signal of fat mass before birth or whether changes in maternal nutrient intake alter plasma leptin concentrations in the fetus. We have therefore investigated the relationship between fetal plasma leptin concentrations and fetal fat mass in pregnant ewes fed at or above maintenance energy requirements.

Fetal leptin influences birth weight in twins with discordant growth.

The objective of this study was to determine the plasma leptin concentrations in twin pregnancies in relation to chorionicity and discordant fetal growth. We studied 53 twin pregnancies of which 26 had growth discordance of > or =20% and 27 were concordant for growth (discordance of < or =10%). Paired maternal and fetal blood samples were obtained at birth. Plasma leptin concentrations were measured by RIA. In discordant monochorionic pregnancies, fetal plasma leptin concentrations in the intrauterine growth-restricted twins were lower than the co-twins with normal growth (mean difference, 3 ng/mL; 95% CI, 2.2 to 3.3 ng/mL; p < 0.001), whereas no such differences were present between concordant monochorionic twin pairs (mean difference, 0.1 ng/mL; 95% CI, -0.2 to 0.5 ng/mL; NS). Similarly, fetal plasma leptin concentrations in appropriate-for-gestational-age twins were higher than in the intrauterine growth-restricted twins of the discordant dichorionic pregnancies (mean difference, 2.4 ng/mL; 95% CI, 1.8 to 3.1 ng/mL; p < 0.001). No such differences were present between the concordant dichorionic twin pairs (mean difference, 0.2 ng/mL; 95% CI, -0.1 to 0.5 ng/mL; NS). Maternal plasma leptin concentrations were comparable among all four groups and were higher than the fetal levels. Fetal plasma leptin concentrations of the intrauterine growth-restricted twins of discordant monochorionic and dichorionic pregnancies were comparable. There was a positive association between cord plasma leptin concentrations and the birth weight of twin pairs (y = 0.002x - 0.32; r = 0.63; p < 0.001; n = 106). A significant positive association was also found between percent differences in birth weight and fetal delta plasma leptin concentrations of the discordant monochorionic and dichorionic twin pairs (y = 0.057x + 0.93; r = 0.60; p < 0.001, n = 26). In conclusion, irrespective of chorionicity, plasma leptin concentrations in intrauterine growth-restricted twins were 2-fold lower than their co-twins with normal growth. These differences may be attributed to placental factors.

Fetal plasma leptin concentrations: relationship with different intrauterine growth patterns from 19 weeks to term.

The relationship between in utero fetal growth and fetal leptin concentrations was investigated between 19 and 41 wk in 40 normal (appropriate for gestational age, AGA) fetuses, in 25 intrauterine growth-restricted (IUGR) fetuses, and in 18 fetuses from gestational diabetic mothers (GDM), representing different intrauterine growth patterns. Umbilical venous plasma leptin concentrations were determined at the time of either in utero fetal blood sampling or delivery. Plasma leptin was measurable as early as 19 wk of gestation. A significant difference was observed between umbilical venous and arterial plasma leptin concentrations (0.6+/-0.6 ng/mL; p<0.01). In AGA and in IUGR fetuses, significant positive relationships were found between fetal leptin concentrations and both gestational age (p<0.001) and fetal weight (p<0.001). Leptin concentrations were significantly higher in AGA than IUGR only after 34 wk (p<0.05), but leptin per kilogram fetal weight (leptin/kg) was not significantly different. In IUGR with abnormal umbilical arterial Doppler velocimetry and fetal heart rate, leptin/kg significantly higher than in IUGR with normal biophysical and biochemical parameters was found (p<0.05). Both circulating plasma leptin and leptin/kg were significantly higher in GDM than in normal fetuses (p<0.001) and correlated with abdominal fat mass measured by ultrasound. No gender differences were observed in any group of fetuses. These findings indicate a clear relationship between fetal leptin concentrations and fetal fat mass. Data in severe IUGR suggest the presence of increased leptin concentrations associated with in utero signs of fetal distress.