It is well established that obesity is associated with dysregulation of the ratio between the two major adipokines leptin and adiponectin. Furthermore, it was recently reported that maternal obesity has a significant impact on placental development. Leptin and adiponectin are present at the fetal-maternal interface and are involved in the development of a functional placenta. However, less is known about leptin and adiponectin’s involvement in the placental alterations described in obese women. Hence, the objective of the present study was to characterize the placental expression and DNA methylation of these two adipokine systems (ligands and receptors) in obese women. Biopsies were collected from the fetal and maternal sides of third-trimester placenta in obese and non-obese (control) women. In both groups, leptin levels were higher on the fetal side than the maternal side, suggesting that this cytokine has a pivotal role in fetal growth. Secondly, maternal obesity (in the absence of gestational diabetes) was associated with (i) elevated DNA methylation of the leptin promoter on fetal side only, (ii) hypomethylation of the adiponectin promoter on the maternal side only, (iii) significantly low levels of leptin receptor protein (albeit in the absence of differences in mRNA levels and promoter DNA methylation), (iv) significantly low levels of adiponectin receptor 1 mRNA expression on the maternal side only, and (v) elevated DNA methylation of the adiponectin receptor 2 promoter on the maternal side only. Our present results showed that maternal obesity is associated with the downregulation of both leptin/adiponectin systems in term placenta, and thus a loss of the beneficial effects of these two adipokines on placental development. Maternal obesity was also associated with epigenetic changes in leptin and adiponectin systems; this highlighted the molecular mechanisms involved in the placenta’s adaptation to a harmful maternal environment.

The placenta exchanges nutrients between the mother and the fetus, and requires a constant abundant energy supply. Adiponectin (a cytokine produced primarily by adipose tissue) controls glucose and lipid homeostasis. It is well known that maternal serum adiponectin levels are inversely related to birth weight suggesting that adiponectin has a negative effect on fetal growth. This effect appears to be related to the control of nutrient transporters in human placenta. However, the underlying molecular mechanisms have not yet been characterized. In the present work, we studied adiponectin's direct effect on human primary cytotrophoblasts from first-trimester placenta. Our result showed that in placental cells, adiponectin (i) inhibits the expression of the major glucose transporters (GLUT1 and GLUT12) and sodium-coupled neutral amino acid transporters (SNAT1, SNAT2, and SNAT4), (ii) enhances total ATP production but decreases lactate production, (iii) inhibits mitochondrial biogenesis and function, and (iv) stimulates cell death by enhancing the expression of the pro-apoptotic B-cell lymphoma-2 (BCL-2)-associated X protein (BAX) and tumor protein P53 (TP53) gene expression and inducing the caspase activity. siRNA mediated down-regulation of adiponectin receptors (ADIPOR1 and ADIPOR2) was used to demonstrate that adiponectin effects on placental nutrient transport and apoptosis seemed to be essentially mediated by these specific receptors. Taken as a whole, these results strongly suggest that adiponectin regulates human placental function by limiting nutrient transporter expression and inducing apoptosis. These findings may help us to better understand adiponectin's role in placental pathologies such as intrauterine growth restriction, which is characterized by fetal weight loss and drastic apoptosis of placental cells.

Human pregnancy needs a correct placentation which depends on adequate cytotrophoblast proliferation, differentiation and invasion. In this study, using specific mitochondrial respiratory chain inhibitors, we observed a decrease of hormone production (hCG and leptin) and cell fusion of human primary villous cytotrophoblasts (CT). These results demonstrated that mitochondria are involved in the control of CT differentiation process. Moreover, we also observed a decrease of mitochondrial mass associated with an increase of mitochondrial DNA during CT differentiation. Furthermore, lactate production increased during CT differentiation suggesting that anaerobic metabolism was enhanced in differentiated CTs, and that the role of mitochondria in CT fusion is not only related to its energetic function. Otherwise, the orphan nuclear receptor, estrogen-related receptor γ (ERRγ) is known to orchestrate transcriptional control of energy metabolism genes. In this study, using RNA knockdown and transcriptional activation with DY131 (an ERRγ agonist), we clearly demonstrated that ERRγ promotes hormone production and cell fusion indicating that ERRγ is a key positive transcriptional factor involved in CT differentiation. Finally, we showed that ERRγ promotes mitochondrial biogenesis and function during CT differentiation, and that the role of ERRγ during trophoblast differentiation is mainly mediated by the control of mitochondrial functions.

PreImplantation Factor (PIF) is a peptide secreted by viable mammalian embryos. Moreover, it can be detected in pregnant women circulation. Recently, it was shown that PIF promotes invasion in trophoblast cell lines in vitro. Successful human embryo implantation depends on a deep and highly controlled invasion of extravillous trophoblast (EVT) in the maternal endometrium. Trophoblast invasion is regulated in part by matrix metalloproteinase (MMP) activity and integrin expression. The present study demonstrates the presence of PIF in early pregnancy and characterizes its effects on primary human trophoblast invasion. At the fetomaternal interface, intense PIF labelling by immunohistochemistry was present during early gestation in villous and extravillous trophoblasts. A decrease of labelling was observed at term. Furthermore, PIF significantly promoted invasion of human EVT isolated from first trimester placenta. The pro-invasive regulatory effect of PIF in EVT was associated with (i) increased matrix metalloproteinase MMP9 activity and (ii) reduced tissue inhibitor of metalloproteinase-1 (TIMP1) mRNA expression. PIF also regulated alpha v and alpha 1 integrin mRNA expressions. Last, the pro-invasive effect of PIF appeared to be mediated by the mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), and the Janus-kinase signal transducer and activator of transcription (JAK-STAT) signaling pathways. In summary, this work describes the direct, positive effect of PIF on the control of human trophoblastic cell invasion by modulating of MMP/TIMP balance and integrin expression. Moreover, these results suggest that PIF is involved in pathological pregnancies characterized by insufficient or excessive trophoblast invasion.

From the earliest stages of gestation, embryonic–maternal interaction has a key role in a successful pregnancy. Various factors present during gestation may significantly influence this type of juxta/paracrine interaction. PreImplantation Factor (PIF) is a recently identified factor with activity at the fetomaternal interface. PIF is secreted by viable embryos and directly controls placental development by increasing the invasive capacity of human extravillous trophoblasts (EVTs). To further specify PIF’s role in the human placenta, we analyzed the genome-wide expression profile of the EVT in the presence of a synthetic PIF analog (sPIF). We found that sPIF exposure altered several pathways related to p53 signaling, survival and the immune response. Functional assays revealed that sPIF acts through the p53 pathway to reduce both early and late trophoblast apoptosis. More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser-15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2-associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels. Furthermore, invalidation experiments of TP53 allowed us to demonstrate that PIF’s effects on placental apoptosis seemed to be essentially mediated by this gene. We have clearly shown that p53 and sPIF pathways could interact in human trophoblast and thus promotes cell survival. Furthermore, sPIF was found to regulate a gene network related to immune tolerance in the EVT, which emphasizes the beneficial effect of this peptide on the human placenta. Finally, the PIF protein levels in placentas from pregnancies affected by preeclampsia or intra-uterine growth restriction were significantly lower than in gestational age-matched control placentas. Taken as a whole, our results suggest that sPIF protects the EVT’s functional status through a variety of mechanisms. Clinical application of sPIF in the treatment of disorders of early pregnancy can be envisioned.

Maternal obesity is increasingly prevalent and is associated with elevated morbidity and mortality rates in both mothers and children. At the interface between the mother and the fetus, the placenta mediates the impact of the maternal environment on fetal development. Most of the literature presents data on the effects of maternal obesity on placental functions and does not exclude potentially confounding factors such as metabolic diseases (e.g., gestational diabetes). In this context, the focus of this review mainly lies on the impact of maternal obesity (in the absence of gestational diabetes) on (i) endocrine function, (ii) morphological characteristics, (iii) nutrient exchanges and metabolism, (iv) inflammatory/immune status, (v) oxidative stress, and (vi) transcriptome. Moreover, some of those placental changes in response to maternal obesity could be supported by fetal sex. A better understanding of sex-specific placental responses to maternal obesity seems to be crucial for improving pregnancy outcomes and the health of mothers and children.