Are leptin and adiponectin involved in recurrent pregnancy loss?

AIM: The aim of this study was to investigate whether recurrent pregnancy loss (RPL) is associated with adipokine gene polymorphisms (namely the leptin -2548 (G/A), adiponectin 276 (G/T), and adiponectin 45 (T/G) polymorphisms) and/or adipokine serum levels. METHODS: A total of 145 women participated in the study. For the analysis of serum adipokine levels, 19 healthy fertile women (control group) and 60 women suffering from RPL were included. For the polymorphism analysis, 126 women suffering from RPL were included. Serum adipokine levels were determined using a commercial radioimmunoassay kit. Adipokine polymorphisms were analyzed using an allele-specific polymerase chain reaction (PCR). RESULTS: Our immunoassays revealed that serum leptin levels were similar in control and RPL groups (17.34 and 20.16 ng/mL, respectively). In contrast, serum adiponectin levels were significantly higher in women with RPL than in controls (9.83 and 6.89 µg/mL, respectively; P < 0.05). Unfortunately, our allele-specific PCR experiments did not reveal any significant differences in allele frequency between women with RPL and NCBI allele frequencies. CONCLUSION: This study demonstrates that adiponectinemia is increased in patients suffering from RPL. However, association of adiponectin with adverse pregnancy outcomes remains to be elucidated.

Adiponectin Inhibits Nutrient Transporters and Promotes Apoptosis in Human Villous Cytotrophoblasts: Involvement in the Control of Fetal Growth.

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 1) inhibits the expression of the major glucose transporters (GLUT1 and GLUT12) and sodium-coupled neutral amino acid transporters (SNAT1, SNAT2, and SNAT4), 2) enhances total ATP production but decreases lactate production, 3) inhibits mitochondrial biogenesis and function, and 4) 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. Small-interfering RNA mediating the 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.

Adiponectin regulates glycogen metabolism at the human fetal­maternal interface

Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e. histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules that are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetal­maternal interface have not yet been characterized. Among the various factors acting at the fetal­maternal interface, we focused on adiponectin ­ an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression, (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions, (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human villous trophoblasts. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetal­maternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta.

Adiponectin limits differentiation and trophoblast invasion in human endometrial cells.

Successful human embryo implantation requires a proper differentiation of endometrial stromal cells (ESCs) into decidual cells, during a process called decidualization. ESCs express specific molecules, such as prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1) and connexin-43. Decidual cells are also involved in the control of trophoblast invasion, by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Adiponectin is an adipokine with insulin-sensitizing, anti-inflammatory and anti-proliferative effects. At the embryo-maternal interface, adiponectin promotes differentiation and invasion of human trophoblastic cells. We hypothesize that the effects of adiponectin on endometrium could counteract its pro-invasive effects previously described in the human trophoblast. In this context, we have firstly demonstrated that adiponectin downregulates IGFBP-1 and connexin-43 mRNA expressions, as well as prolactin secretion in ESCs, suggesting an anti-differentiative effect of adiponectin. Secondly, we found that invasive capacities of trophoblastic cell line HTR-8/SVneo are reduced in the presence of conditioned media from ESC cultured in the presence of adiponectin. Adiponectin's anti-invasive action is associated with a decreased activity of MMP-2 and MMP-9, and an increased TIMP-3 mRNA expression in ESCs. Finally, adiponectin receptors (ADIPOR1 and ADIPOR2) knockdown abolishes the anti-differentiative and anti-invasive effects of adiponectin in human ESCs. Altogether, our results suggest that adiponectin reduces the decidualization process and inversely induces the production of endometrial factors that limit trophoblast invasion. Thus, through a dual control in trophoblast and endometrial cells, adiponectin appears as a pivotal actor of the embryo implantation process.

The roles of leptin and adiponectin at the fetal-maternal interface in humans.

Infertility now affects one in seven couples, and the prevalence of this condition continues to increase. Ovulatory defects and unknown causes account for more than half of the cases of infertility. It has been postulated that a significant proportion of these cases are directly or indirectly related to obesity, since the presence of excess adipose tissue has a variety of effects on reproductive function. Here, we review on the effects of the two major adipokines (leptin and adiponectin) on fertility, with a focus on the first steps in embryo implantation and the key components of fetal-maternal interface (the placenta and the endometrium). These adipokines are reportedly involved in the regulation of cell proliferation and differentiation, and as such affect local angiogenesis, immune tolerance and inflammatory processes in placental and endometrial tissues. In placental cells, leptin and adiponectin also modulate trophoblast invasiveness and the nutrient supply. These observations strongly suggest by interfering with the placenta and endometrium, adipokines can create a favorable environment for embryo implantation and have a key role in fetal-maternal metabolism, fetal-maternal communication, and gestation. Given that reproductive functions are tightly coupled to the energy balance, metabolic abnormalities may lead to the development of complications of pregnancy and changes in fetal growth. In this context, we suggest that the leptin/adiponectin ratio may be a clinically valuable marker for detecting a number of pathologies in pregnancy.

Involvement of estrogen-related receptor-γ and mitochondrial content in intrauterine growth restriction and preeclampsia.

OBJECTIVE: To measure mitochondrial content and the expression of estrogen-related receptor-γ (ERRγ, a major inducer of mitochondrial biogenesis) in placentas from women with intrauterine growth restriction (IUGR) associated or not with pre-eclampsia (PE), relative to control placentas. DESIGN: Case-control study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Thirty-nine placentas from women with IUGR, 8 IUGR+PE, and 30 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mitochondrial DNA and protein content, gene and protein expression. RESULT(S): We observed significantly lower placental mitochondrial DNA and protein contents (associated with down-regulation of ERRγ expression) in IUGR and IUGR+PE placentas, relative to control placentas. Our results also revealed that the placental mitochondrial DNA content was directly correlated with fetal weight. Moreover, we observed significantly lower peroxisome proliferator-activated receptor-γ coactivator-1α and sirtuin 1 messenger RNA expression levels in IUGR+PE placentas, relative to control placentas. CONCLUSION(S): The low mitochondrial DNA and protein contents observed in IUGR placentas are probably due to down-regulation of ERRγ expression. This finding suggests that ERRγ has a major role in the control of placental development.