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.

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.

Trophoblast syncytialisation necessitates mitochondrial function through estrogen-related receptor-γ activation.

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.