Mol. Hum. Reprod. Advance Access originally published online on July 26, 2006
Molecular Human Reproduction 2006 12(9):551-556; doi:10.1093/molehr/gal064
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Relationships between maternal plasma leptin, placental leptin mRNA and protein in normal pregnancy, pre-eclampsia and intrauterine growth restriction without pre-eclampsia
1Magee-Womens Research Institute, 2Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA, 3Department of Clinical Genetics, Helsinki University Central Hospital, 4Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, Finland and 5Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
6 To whom correspondence should be addressed at: Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki, PO Box 63, FIN-00014, Finland. E-mail: hannele.laivuori{at}helsinki.fi
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Leptin, an adipocyte hormone involved in energy homeostasis, is important in reproduction and pregnancy. Questions yet to be addressed include the source of higher leptin during pregnancy and its relationship to pregnancy outcome and fetal growth. The objective of this study was to investigate the relationship between placental leptin gene expression, placental leptin protein concentration and maternal plasma leptin concentration among control pregnant women, women with pre-eclampsia and women with growth-restricted infants. We also investigated the relationship between placental leptin expression and the placental expression of enzymes involved in cellular lipid balance: fatty acid translocase (CD36), carnitine palmitoyltransferase I (CPT-1B) and lipoprotein lipase (LPL). Placental leptin expression, placental protein and maternal plasma concentration were higher in pre-eclampsia than in controls but not in women with growth-restricted infants. Placental leptin expression and placental protein were higher in the preterm pre-eclamptic subjects, whereas maternal leptin was higher in the term pre-eclamptic subjects. The placental gene expression of CD36, CPT-1B and LPL were not different among the groups. This study suggests that despite similar failed placental bed vascular remodelling in pre-eclampsia and intrauterine growth restriction (IUGR), leptin gene expression is higher only in preterm pre-eclampsia.
Key words: intrauterine growth restriction/leptin/placenta/pre-eclampsia/pregnancy
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Pre-eclampsia is a common pregnancy-specific syndrome (3–5% of pregnancies), which is one of the major causes of maternal and perinatal morbidity and mortality worldwide. It places great demands for maternity care because the onset and clinical course are unpredictable, and there is currently no predictive test available. The aetiology is unknown, but the placenta is essential for the disease process. The only treatment is delivery, which often causes iatrogenic prematurity. Pre-eclampsia is diagnosed by the new appearance of increased blood pressure and proteinuria in late pregnancy (Roberts and Lain, 2002
). Pre-eclampsia can be considered as a two-stage disease (Roberts, 2003). The first stage is a reduction in fetal–placental perfusion, frequently secondary to abnormal implantation. The second stage is the maternal syndrome. However, the first stage does not always result in the second stage. Placental bed biopsies examined with conventional histological techniques indicate similar reduced vascular remodelling and abnormal implantation in pre-eclampsia, intrauterine growth restriction (IUGR) and preterm births that are not associated with infection (Khong et al., 1986; Arias et al., 1993). IUGR is not invariably associated with pre-eclampsia even if non-perfusion perturbing abnormalities such as infection and fetal anomalies are excluded.
We propose that reduced placental perfusion generates fetal–placental signals that influence maternal metabolism and physiology which may influence nutrient delivery and affect fetal growth. We hypothesize that some women cannot tolerate this signal and will develop pre-eclampsia, whereas an inadequate signal results in IUGR without the maternal syndrome. The hormone leptin may act as such a pregnancy signal. Leptin is secreted by adipose tissue and during pregnancy by the placenta (Masuzaki et al., 1997). The proposed roles for leptin in pregnancy include the regulation of fetal growth, placental angiogenesis, growth and immunomodulation, as well as mobilization of maternal fat (Hoggard et al., 2001). According to placental perfusion studies, 98.4% of placental leptin is released into the maternal circulation (Linnemann et al., 2000). Total and free leptin concentrations are higher in maternal blood during pregnancy and further elevated in pre-eclampsia (McCarthy et al., 1999; Laivuori et al., 2000; Teppa et al., 2000). Therefore, leptin could be one of the fetal–placental signals altering maternal metabolism to benefit the fetus by mobilizing nutrients.
The objective of this study was to quantify and investigate the relationship between placental leptin gene expression, placental leptin protein and maternal plasma leptin among control pregnant women, women with pre-eclampsia and women with growth-restricted infants. We further investigated the relationship between placental leptin expression and the placental expression of enzymes involved in cellular lipid balance: fatty acid translocase (CD36), a transporter of the long-chain fatty acids (Febbraio et al., 2001); carnitine palmitoyltransferase I (CPT-1B), a mitochondrial fatty acid transport protein and regulator of ß-oxidation (Wang et al., 1999); and lipoprotein lipase (LPL), a regulator of triglyceride hydrolysis (Herrera, 2002).
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Subjects and sample acquisition
With the permission of the Institutional Review Board (IRB), we studied placenta samples from 79 women who provided written informed consent. Twenty-one pre-eclamptic women were matched as a group by maternal age, gestational age at delivery, pre-pregnancy BMI, parity and race with 20 women with uncomplicated pregnancies (controls for pre-eclampsia) (Table I). Similarly, 20 women with IUGR infants were matched as a group with 18 women with uncomplicated pregnancies (controls for IUGR) (Table I). Placenta samples were acquired as a part of Prenatal Exposures and Pre-eclampsia Prevention (PEPP) project and were collected between 12 April 1998 and 16 November 2000. Women with pre-existing diabetes were excluded from the study population. Smoking status was available from only 9 women in the pre-eclampsia group, 17 women in controls for pre-eclampsia, 19 women in the IUGR group and 18 women in the controls for IUGR. Therefore, we were not able to match groups by smoking status. Three women in the pre-eclampsia group, 9 women in controls for pre-eclampsia, 14 women in the IUGR group and 8 women in the controls for IUGR were smokers. Systolic and diastolic blood pressures were not significantly different between the pre-eclampsia group and controls for pre-eclampsia before 20 weeks of gestation but were significantly elevated at delivery in the pre-eclampsia group (Table I). Systolic and diastolic blood pressures were not significantly different between the IUGR group and controls for IUGR before 20 weeks of gestation or at delivery (Table I). Ten women in the pre-eclampsia group delivered preterm (before 37 weeks of gestation) compared with eight controls for pre-eclampsia (P = 0.62). All women in the IUGR group and controls for IUGR delivered at term. Glucocorticoids were administered to one woman in the pre-eclampsia group and to two controls for pre-eclampsia who delivered before 33 weeks of gestation (P = 0.61). The birthweight centiles were corrected for gestational age, race and sex for our population and were lower in the pre-eclampsia group and the IUGR group compared with controls (Table I). Four women in the pre-eclampsia group (19%) delivered IUGR infants, and all these deliveries were preterm (40% of the preterm pre-eclampsia).
|
All pre-eclamptic women met the criteria of hypertension, proteinuria and hyperuricaemia. Hypertension was defined as an increase of 30 mmHg systolic or 15 mmHg diastolic blood pressure compared with values obtained before 20 weeks of gestation or an absolute blood pressure of 140 and/or 90 mmHg after 20 weeks of gestation, if earlier blood pressures were unknown. Among the pre-eclamptic women, 71.4% had an absolute blood pressure of 140 mmHg systolic or 90 mmHg diastolic in addition to the diagnostic incremental blood pressure increase. Proteinuria was defined as >300 mg per 24-h collection, >+2 on a voided or >+1 on a catheterized random urine specimen or >0.3 for the urine protein/creatinine ratio. Hyperuricaemia was defined as >1 SD above the mean value for the gestational age at which the sample was obtained. IUGR was defined as the birthweight below tenth centile for the gestational age corrected for race and sex for our population.
Placenta samples were obtained at the time of vaginal delivery (73 samples) or Caesarean section (6 samples). Tissues were rinsed in saline, frozen in liquid nitrogen and then stored at –80°C until use. Maternal EDTA plasma samples were obtained at the time of admission for delivery. Samples were stored at –80°C for later analysis.
RNA isolation and reverse transcription
RNA was extracted using RNAwizTM reagent (Ambion, Austin, TX, USA) according to the manufacturer’s instructions. The amount of RNA was measured spectrophometrically by the absorbance at 260 nm. The purity of the RNA was estimated by the ratio of the absorbance at 260/280 nm. The quality of the RNA samples was determined with denaturing agarose gels and staining with ethidium bromide. The placenta total RNA (400 ng) was reverse transcribed to cDNA in 20 µl volume using Taqman Reverse Transcription Reagents (Applied Biosystems, Foster City, CA, USA). Final reaction conditions were x1 Taqman buffer, 5.5 mM MgCl, 500 µU of each dNTP, 2.5 µM random hexamers, 0.4 U/µl ribonuclease inhibitor and 1.25 U/µl MultiScribe reverse transcriptase. Reaction mixture was incubated at 25°C for 10 min, 48°C for 30 min and heat-inactivated at 95°C for 5 min. The human placenta total RNA (2 µg) (FirstChoiseTM Total RNA; Ambion) was reverse transcribed to complementary cDNA in 100 µl volume using Taqman Reverse Transcription Reagents (Applied Biosystems) to create standard curves in the real-time RT–PCR step. The efficiency of the reverse transcription was estimated to be 70%.
Real-time RT–PCR
To monitor gene expression, we used semi-quantitative real-time PCR analysis. All PCR reactions were performed using an ABI Prism 7700 Sequence Detection System (Applied Biosystems). The threshold cycle (Ct) reflects the cycle number at which the fluorescence generated in the reaction crosses a pre-selected threshold and is inversely related to the concentration of cDNA prior to amplification. We compared Ct values of the samples with a standard curve constructed by serial dilutions of the human placenta total RNA.
Primers and probes
We used SYBR Green chemistry to analyse leptin, CD36 and CPT-1B gene expression and amplified ß-actin as an endogenous control. Primers were chosen using the Primer Express software version 1.5a (Applied Biosystems). To avoid the amplification of the genomic DNA, all the target gene forward and reverse primers were selected to be in different exons, except ß-actin, in which case the forward primer was selected at the junction between two exons. We conducted standard nucleotide BLAST to confirm the specificity of the primers, and we checked the absence of single nucleotide variations. The LPL gene expression was analysed using Taqman chemistry, and ß-actin was amplified as an endogenous control. We used minor groove-binding (MGB) DNA oligonucleotide (TaqMan MGB probe), which forms hyper-stabilized duplexes with cDNA. Primers and probe for LPL gene were chosen using the Primer Express software version 1.5a (Applied Biosystems) (Table II) following the user-bulletin guidelines for the design of MGB probes. All primers were from University of Pittsburgh DNA Synthesis Facility. LPL TaqMan MGB probe was bought from Applied Biosystems Custom Oligo Synthesis Service (Foster City, CA). Commercial pre-developed assay reagents (x20 primer and MGB probe mix) were used to detect ß-actin (Applied Biosystems) and to obtain a normalized LPL gene value.
|
PCR amplification
In PCR reactions for leptin, CD36, CPT-1B and ß-actin (25 µl), we used x1 SYBR® Green PCR Master mix (Applied Biosystems), 300 nM of each primer and 3.5 ng (1:20 dilution, 5 µl volume) cDNA template. In PCR reactions for LPL (25 µl), we used x1 TaqMan® PCR Master mix (Applied Biosystems), 900 nM of each primer, 250 nM TaqMan MGB probe and 3.5 ng cDNA template. In PCR reactions for ß-actin used to normalize LPL gene expression (25 µl), we used x1 TaqMan® PCR Master mix (Applied Biosystems), x1 Human ß-actin Control Mix (Applied Biosystems) and 3.5 ng cDNA template. The thermal cycling conditions were 50°C for 2 min (for carry-over prevention with Uracil-N-glycosylase) and an initial denaturation step at 95°C for 10 min, followed by 40 cycles at 95°C for 15 s and 60°C for 1 min.
Melting curve analysis of SYBR Green assays
Because SYBR Green binds to any double-stranded DNA, the specificity of the product and absence of primer dimers and other non-specific products were confirmed with the additional run for melting curves after PCR amplification. The SYBR Green fluorescence of generated products was continuously monitored throughout temperature ramp from step 60°C to 95°C for 19 min 59 s. After data recording, a Sequence Detection Software version 1.7a (Applied Biosystems) multicomponent file was exported to Dissociation Curves 1.0 software (Applied Biosystems) for the melting curve analysis. The selected conditions and primers resulted in amplification of a single species of cDNA.
Analysis of cDNA samples
All samples were run in duplicate in a 96-well plate for the target gene and ß-actin. For each sample, the amount of the target gene and the endogenous control was determined from the standard curves run in the same plate. The target gene amount was divided by the endogenous control amount to obtain the normalized target gene value.
Real-time RT–PCR standard curve construction
The standard curves using the four concentrations were performed in duplicate for each target gene and ß-actin. Dilutions were made to produce a standard curve covering the concentration range 70–70 000 pg of total placenta RNA per well for leptin and CD36, 350–70 000 pg for CPT-1B and 700–70 000 pg for LPL. Inter-assay variation for standards were 4.6% for leptin, 2.2% for CD36, 5.4% for CPT-1B, 1.2% for LPL, 3.6% for ß-actin (SYBR Green chemistry) and 1.4% for ß-actin (TaqMan chemistry). The standard curves displayed a linear correlation of 0.96–1.00. The efficiency of the reaction (E) was calculated using the formula E = 101/m – 1, where m is the slope of the standard curve. The mean E was 78% for the leptin reactions, 64% for the LPL reactions, 57% for the CD36 reactions, 61% for the CPT-1B reactions, 67% for the ß-actin reactions (SYBR Green) and 66% for the ß-actin reactions (TaqMan).
Quantification of plasma leptin
Total plasma leptin was quantified by radioimmunoassay using the commercial RIA from Linco Research Inc. (St. Charles, Missouri, catalog # HL-81K). All samples were run in duplicate. The average coefficient of variation between runs was 7.1%.
Preparation of placental homogenates and placental leptin quantification
Homogenates of placental tissue were prepared from the rinsed and flash-frozen placental tissue discussed previously. Briefly, placental homogenates were prepared by homogenizing the tissue in 1:2.5 (grams tissue : millilitre volume) in HEPES–Mannitol–Magnesium buffer (300 mM Mannitol, 1 mM MgSO4·7H2O and 10 mM HEPES) (pH 7.4) at 4°C. The homogenate was centrifuged at 23 000 x g for 40 min, and the supernatant was collected and assayed for total protein and leptin. Placental leptin protein was quantified using an enzyme-linked immunosorbent assay (ELISA) from Linco Research Inc. (St. Charles, Missouri, catalog # EZHL-80SK). All samples were run in duplicate. The inter-assay coefficient of variation was <10%. Placental leptin protein was normalized to the total protein concentration of the supernatant of the placental homogenate. Protein quantification was determined by the Bradford method and standardized to known quantities of bovine serum albumin (BSA).
Statistical analysis
Statistical analysis was performed using Stat-View 4.5 software (Abacus Concepts, Berkeley, CA, USA). Data are presented as mean ± SEM unless otherwise indicated. Parametric and non-parametric tests were used as appropriate for the continuous clinical data. Categorical data were analysed using Chi-square or Fisher’s exact test. Comparisons of the gene expression and leptin measurements between the four groups were conducted using analysis of variance (ANOVA) and Fisher’s protected least significant difference (PLSD) post hoc test. The square root transformation was performed to normalize the distribution of the data. The Spearman rank correlation coefficient was used to analyse leptin gene expression and birthweight centiles. Statistical significance was accepted at P < 0.05 for all comparisons.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The ratio of placental leptin/ß-actin mRNA was higher in pre-eclampsia cases (4.99 ± 1.38) compared with controls for pre-eclampsia (1.65 ± 0.32, P = 0.015), IUGR cases (1.27 ± 0.30, P = 0.002) and controls for IUGR (2.37 ± 0.77, P = 0.028) (Table III). Similarly, the concentration of placental leptin protein and maternal plasma leptin were higher in the pre-eclampsia cases compared with controls for pre-eclampsia (Table III), and there was no difference in placental leptin protein and maternal plasma leptin between the IUGR cases and the controls for IUGR (Table III).
|
The ratio of placental leptin/ß-actin mRNA was higher in those pre-eclamptic patients who delivered preterm [<37 weeks of gestation, n = 10, gestational age = 34.8 ± 0.45 weeks (mean ± SE)] (7.23 ± 2.02 leptin/ß-actin ratio) compared with pre-eclamptic patients who delivered at term (n = 11, 38.2 ± 0.43 weeks, P < 0.0001 versus preterm pre-eclampsia) (2.95 ± 1.74 leptin/ß-actin ratio, P = 0.005), controls for pre-eclampsia who delivered preterm (n = 8, 2.00 ± 0.67 leptin/ß-actin ratio, P = 0.007) and controls for pre-eclampsia who delivered at term (n = 12, 1.42 ± 0.31 leptin/ß-actin ratio, P = 0.001) (Figure 1A). Furthermore, when divided into term and preterm deliveries, the concentration of placental leptin protein was higher in the preterm pre-eclamptic cases (1.29 ± 0.22 ng/mg protein) compared with the term controls (0.59 ± 0.16 ng/mg protein, P = 0.04) (Figure 1B). In contrast, maternal plasma leptin was not different between term and pre-term pre-eclampsia (P = 0.48) and was higher in the term pre-eclamptic cases (51.3 ± 8.6 ng/ml) compared with the term controls (28.4 ± 3.6 ng/ml, P = 0.02) (Figure 1C), while differences between preterm pre-eclamptics and their controls did not achieve statistical significance (P = 0.09).
|
Placental leptin gene expression correlated negatively with the birthweight centiles in the pre-eclampsia cases (Spearman r = –0.45, P = 0.03), whereas no correlation was seen in the IUGR cases (Spearman r = –0.03, P = 0.89). Placental leptin protein and maternal plasma leptin did not correlate with birthweight centile in the pre-eclamptic cases or IUGR cases.
There were no significant differences in ratios of CPT-1B/ß-actin, CD36/ß-actin or LPL/ß-actin mRNA ratios between pre-eclampsia cases, IUGR cases and their respective control groups (data not shown).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The role of increased maternal leptin during human pregnancy is unclear; however, it has been hypothesized to be important in fetal growth, and we speculate that it may serve as a possible signal to alter maternal metabolism to benefit the fetus. In this study, we found that placental leptin expression, placental leptin protein and plasma leptin are all higher in women with pre-eclampsia but not different among women with IUGR infants compared with controls, and the elevation in placental leptin expression and protein is primarily in women with preterm pre-eclampsia; however, the increase in plasma leptin is primarily in the women with term pre-eclampsia.
We found a significant increase in leptin gene expression in the placental tissue of women with preterm pre-eclampsia compared with pregnancies complicated by term pre-eclampsia or IUGR or with gestational age-matched controls. Furthermore, leptin gene expression was not different between the two control groups with 3-week difference in the gestational age, and there were no differences in frequency of glucocorticoid administration, which is known to affect leptin expression (Miell et al., 1996). Higher placental leptin expression has been reported in pre-eclampsia previously, but no distinction was made between preterm and term (Li et al., 2004). In addition, similar to our study, Bersinger and co-workers reported no differences in placental leptin protein concentrations in term pre-eclampsia compared with controls (Bersinger et al., 2002). Furthermore, we report finding an increase in maternal plasma leptin in pre-eclampsia similar to several previous studies (McCarthy et al., 1999; Laivuori et al., 2000; Teppa et al., 2000; Sagawa et al., 2002).
Why are placental leptin gene expression and leptin protein increased in preterm pre-eclampsia? It has been suggested that placental production of leptin is augmented in pre-eclampsia because of placental hypoxia, which is a consequence of reduced placental perfusion (Mise et al., 1998). Indeed, it has been shown in trophoblast-derived BeWo cells that leptin gene expression is up-regulated by hypoxia through a transcriptional mechanism likely to involve distinct hypoxia-responsive cis-acting sequences in the promoter (Grosfeld et al., 2001). However, our finding that placental leptin gene expression is not different in IUGR pregnancies that are also presumably hypoxic compared with controls suggests that there are likely additional contributing factors to placental leptin expression. One such factor could be insulin. A large (3- to 5-fold) augmentation in placental leptin message and protein has been reported in insulin-treated diabetic women (Lepercq et al., 1998). In addition, prolonged exposure to insulin increases plasma leptin concentrations in humans (Kolaczynski et al., 1996; Malmström et al., 1996). Pre-eclampsia is a state of hyperinsulinaemia and increased insulin resistance (Kaaja et al., 1999), and it is tempting to speculate that maternal hyperinsulinaemia is also important in the up-regulation of placental leptin gene expression in this condition. Another possibility is that inflammatory stimuli may up-regulate leptin expression (Sarraf et al., 1997). The inflammatory response is already well developed in normal pregnancy and further elevated in pre-eclampsia (Redman et al., 1999), and leptin gene expression is higher in inflammation and plays a key role in immune response and T-cell activation (Zarkesh-Esfahani et al., 2004; Otero et al., 2005; Sennello et al., 2005). The fact that the main difference occurs in preterm pre-eclampsia may suggest a greater importance for inflammation in preterm pre-eclampsia. It is also possible that the placental cells relevant to leptin production are not hypoxic in IUGR. The syncytiotrophoblast is the site of placental leptin production (Senaris et al., 1997), and in at least severe IUGR, the intervillous blood to which syncytiotrophoblast is exposed is hyperoxic as a result of reduced oxygen extraction (Kingdom and Kaufmann, 1999).
The placenta is a target of leptin action as well as a source for leptin synthesis (Hassink et al., 1997; Henson et al., 1998). Leptin and its receptors co-exist in the syncytiotrophoblast (Challier et al., 2003). The location of transmembrane leptin-receptor isoforms on placental cells facing the maternal circulation implies that receptors are likely to bind maternal circulating leptin (Challier et al., 2003). Furthermore, a recent study has demonstrated that leptin is capable of stimulating placental amino acid transport that is likely to be of benefit to fetal growth (Jansson et al., 2003). However, placental leptin gene expression was inversely correlated with infant birthweight centile in the pre-eclamptic cases but not the IUGR cases or controls. In addition, maternal plasma leptin and placental leptin protein did not correlate with birthweight centile in any of the groups. These relationships suggest that the effect of leptin, if any, on fetal growth is not simple; and the investigation of the effect of leptin on specific pathways important to fetal growth (such as amino acid or lipid transport) is likely to provide greater insight into its biological relevance. To this end, we examined the gene expression of three enzymes involved in cellular lipid balance: CD36, a transporter of the long-chain fatty acids; CPT-1B, a regulator of ß-oxidation; and LPL, a regulator of triglyceride hydrolysis. However, in contrast to leptin, we did not observe any differences in the expression of these enzymes between the four groups.
This study indicates that placental leptin expression and protein production are higher in pre-eclampsia, particularly preterm, and this is in contrast to IUGR in the absence of pre-eclampsia. Furthermore, the increase in placental leptin likely contributes to increases in maternal plasma leptin. Lastly, the action of leptin on placental function is likely to be significant; however, this area requires further investigation.
|
Acknowledgements |
|---|
We thank Lisa M. Bodnar Ph.D., M.P.H., R.D. for statistical assistance. This study was supported by grants from the Academy of Finland, the Finnish Medical Society Duodecim, the Helsingin Sanomat Centennial Foundation, the Jalmari and Rauha Ahokas Foundation and the Magee-Women’s Research Institute Fellowship Program (MWH-CRC grant 5MO1 RR00056) and NIH grants P01 HD30367-07, RO1 HL64144-03 and 1S10RR15912.
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Arias F, Rodriquez L, Rayne SC and Kraus FT (1993) Maternal placental vasculopathy and infection: two distinct subgroups among patients with preterm labor and preterm ruptured membranes. Am J Obstet Gynecol 168,585–591.[Web of Science][Medline]
Bersinger NA, Groome N and Muttukrishna S (2002) Pregnancy-associated and placental proteins in the placental tissue of normal pregnant women and patients with pre-eclampsia at term. Eur J Endocrinol 147,785–793.[Abstract]
Challier J, Galtier M, Bintein T, Cortez A, Lepercq J and Hauguel-de Mouzon S (2003) Placental leptin receptor isoforms in normal and pathological pregnancies. Placenta 24,92–99.[CrossRef][Web of Science][Medline]
Febbraio M, Hajjar DP and Silverstein RL (2001) CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 108,785–791.[CrossRef][Web of Science][Medline]
Grosfeld A, Turban S, Andre J, Cauzac M, Challier JC, Hauguel-de Mouzon S and Guerre-Millo M (2001) Transcriptional effect of hypoxia on placental leptin. FEBS Lett 502,122–126.[CrossRef][Web of Science][Medline]
Hassink SG, de Lancey E, Sheslow DV, Smith-Kirwin SM, O’Connor DM, Considine RV, Opentanova I, Dostal K, Spear ML, Leef K et al. (1997) Placental leptin: an important new growth factor in intrauterine and neonatal development? Pediatrics 100,e1.
Henson MC, Swan KF and O’Neil JS (1998) Expression of placental leptin and leptin receptor transcripts in early pregnancy and at term. Obstet Gynecol 92,1020–1028.[CrossRef][Web of Science][Medline]
Herrera E (2002) Implications of dietary fatty acids during pregnancy on placental, fetal and postnatal development—a review. Placenta 23,S9–S19.
Hoggard N, Haggarty P, Thomas L and Lea RG (2001) Leptin expression in placental and fetal tissues: does leptin have a functional role? Biochem Soc Trans 29,57–63.[CrossRef][Web of Science][Medline]
Jansson N, Greenwood SL, Johansson BR, Powell TL and Jansson T (2003) Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. J Clin Endocrinol Metab 88,1205–1211.
Kaaja R, Laivuori H, Laakso M, Tikkanen MJ and Ylikorkala O (1999) Evidence of a state of increased insulin resistance in preeclampsia. Metabolism 48,892–896.[CrossRef][Web of Science][Medline]
Khong TY, De Wolf F, Robertson WB and Brosens I (1986) Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 93,1049–1059.[Web of Science][Medline]
Kingdom JC and Kaufmann P (1999) Oxygen and placental vascular development. Adv Exp Med Biol 474,259–275.[Web of Science][Medline]
Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J and Caro JF (1996) Acute and chronic effects of insulin on leptin production in humans. Diabetes 45,699–701.[Abstract]
Laivuori H, Kaaja R, Koistinen H, Karonen SL, Andersson S, Koivisto V and Ylikorkala O (2000) Leptin during and after preeclamptic or normal pregnancy: its relation to serum insulin and insulin sensitivity. Metabolism 49,259–263.[CrossRef][Web of Science][Medline]
Lepercq J, Cauzac M, Lahlou N, Timsit J, Girard J, Auwerx J and Hauguel-de Mouzon S (1998) Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes 47,847–850.[Abstract]
Li RH, Poon SC, Yu MY and Wong YF (2004) Expression of placental leptin and leptin receptors in preeclampsia. Int J Gynecol Pathol 23,378–385.[Web of Science][Medline]
Linnemann K, Malek A, Sager R, Blum WF, Schneider H and Fusch C (2000) Leptin production and release in the dually in vitro perfused human placenta. J Clin Endocrinol Metab 85,4298–4301.
Malmström R, Taskinen M-R, Karonen S-L and Yki-Järvinen H (1996) Insulin increases plasma leptin concentrations in normal subjects with NIDDM. Diabetologia 39,993–996.[Medline]
Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T et al. (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3,1029–1033.[CrossRef][Web of Science][Medline]
McCarthy JF, Misra DN and Roberts JM (1999) Maternal plasma leptin is increased in preeclampsia and positively correlates with fetal cord concentration. Am J Obstet Gynecol 180,731–736.[CrossRef][Web of Science][Medline]
Miell JP, Englaro P and Blum WF (1996) Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human subjects. Horm Metab Res 28,704–707.[Web of Science][Medline]
Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H, Mori T, Masuzaki H, Hosoda K, Ogawa Y et al. (1998) Augmented placental production of leptin in preeclampsia: possible involvement of placental hypoxia. J Clin Endocrinol Metab 83,3225–3229.
Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, Gomez-Reino JJ and Gualillo O (2005) Leptin, from fat to inflammation: old questions and new insights. FEBS Lett 579,295–301.[CrossRef][Web of Science][Medline]
Redman CW, Sacks GP and Sargent IL (1999) Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstetrics Gynecol 180,499–506.[CrossRef][Web of Science][Medline]
Roberts JM (2003) Pre-Eclampsia: A Two-Stage Disorder. RCOG Press, London.
Roberts JM and Lain KY (2002) Recent insights into the pathogenesis of pre-eclampsia. Placenta 23,359–372.[CrossRef][Web of Science][Medline]
Sagawa N, Yura S, Itoh H, Mise H, Kakui K, Korita D, Takemura M, Nuamah MA, Ogawa Y, Masuzaki H et al. (2002) Role of leptin in pregnancy—a review. Placenta 23,S80–S86.
Sarraf P, Frederich RC, Turner EM, Ma G, Jaskowiak NT, Rivet DJ III, Flier JS, Lowell BB, Fraker DL and Alexander HR (1997) Multiple cytokines and acute inflammation raise mouse leptin levels: potential role inflammatory anorexia. J Exp Med 185,171–175.
Senaris R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Considine RV, Dieguez C and Casanueva FF (1997) Synthesis of leptin in human placenta. Endocrinology 138,4501–4504.
Sennello JA, Fayad R, Morris AM, Eckel RH, Asilmaz E, Montez J, Friedman JM, Dinarello CA and Fantuzzi G (2005) Regulation of T cell-mediated hepatic inflammation by adiponectin and leptin. Endocrinology 146,2157–2164.
Teppa RJ, Ness RB, Crombleholme WR and Roberts JM (2000) Free leptin is increased in normal pregnancy and further increased in preeclampsia. Metabolism 49,1043–1048.[CrossRef][Web of Science][Medline]
Wang MY, Lee Y and Unger RH (1999) Novel form of lipolysis induced by leptin. J Biol Chem 274,17541–17544.
Zarkesh-Esfahani H, Pockley AG, Wu Z, Hellewell PG, Weetman AP and Ross RJ (2004) Leptin indirectly activates human neutrophils via induction of TNF-alpha. J Immunol 172,1809–1814.
Submitted on April 25, 2006; resubmitted on June 18, 2006; accepted on June 26, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Herse, Bai Youpeng, A. C. Staff, J. Yong-Meid, R. Dechend, and Zhou Rong Circulating and Uteroplacental Adipocytokine Concentrations in Preeclampsia Reproductive Sciences, June 1, 2009; 16(6): 584 - 590. [Abstract] [PDF]
|
|
|
|
 |
|
 P. Cunningham and L. McDermott Long Chain PUFA Transport in Human Term Placenta J. Nutr., April 1, 2009; 139(4): 636 - 639. [Full Text] [PDF]
|
|
|
|
 |
|
 V. D. Winn, M. Gormley, A. C. Paquet, K. Kjaer-Sorensen, A. Kramer, K. K. Rumer, R. Haimov-Kochman, R.-F. Yeh, M. T. Overgaard, A. Varki, et al. Severe Preeclampsia-Related Changes in Gene Expression at the Maternal-Fetal Interface Include Sialic Acid-Binding Immunoglobulin-Like Lectin-6 and Pappalysin-2 Endocrinology, January 1, 2009; 150(1): 452 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-w. Yung, S. Calabrese, D. Hynx, B. A. Hemmings, I. Cetin, D. S. Charnock-Jones, and G. J. Burton Evidence of Placental Translation Inhibition and Endoplasmic Reticulum Stress in the Etiology of Human Intrauterine Growth Restriction Am. J. Pathol., August 1, 2008; 173(2): 451 - 462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Raso, G. Bianco, A. Iacono, E. Esposito, G. Autore, M. C. Ferrante, A. Calignano, and R. Meli Maternal adaptations to pregnancy in spontaneously hypertensive rats: leptin and ghrelin evaluation J. Endocrinol., September 1, 2007; 194(3): 611 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Herse, R. Dechend, N. K. Harsem, G. Wallukat, J. Janke, F. Qadri, L. Hering, D. N. Muller, F. C. Luft, and A. C. Staff Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia Hypertension, March 1, 2007; 49(3): 604 - 611. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||