Abstract
Glucose transporter isoform-3 (GLUT3), one of the primary placental facilitative glucose transporters responsible for basal glucose transport, has a crucial role in glucose transport and fetal growth during early pregnancy. A GLUT3 mutation in mice has been reported to cause loss of early pregnancy or late-gestational fetal growth restriction. However, the underlying mechanisms that regulate the placental GLUT3 transporter in humans are largely unknown. In the present study, we used the JEG-3 human choriocarcinoma cell line, which resembles a first trimester placental model, to study the role of the mammalian target of rapamycin complex 1 (mTORC1) in the regulation of placental GLUT3. We combined rapamycin treatment and small interfering (si) RNA-mediated silencing approaches with mRNA and protein expression/localization studies to investigate the alteration of GLUT3 expression and localization following mTORC1 inhibition in JEG-3 trophoblasts. Inhibition of mTORC1 signaling by silencing raptor decreased GLUT3 mRNA expression (−41%) and protein expression (−50%). Similar effects were obtained in cells in which mTORC1 was inhibited by rapamycin. Immunofluorescence analysis revealed that GLUT3 expression was markedly reduced in the cell surface and cytoplasm of JEG-3 cells in response to mTORC1 silencing. Because placental mTORC1 activity and GLUT3 expression are decreased in human intrauterine growth restriction, our data suggested one possible mechanism for the abnormal fetal growth in this pregnancy complication.
Highlights
Inadequate nutrient supply from the mother to the fetus leads to abnormal intrauterine fetal growth, which may increase the risk for health problems, including obesity, diabetes and cardiovascular disease in both childhood and later life [1]
No changes were observed in the total 4E-BP1 (n = 4, p = 0.149) and S6K1expression (n = 4, p = 0.304) in rapamycin-treated cells compared with the control cells (Figure 1A)
We demonstrated that changes in placental mammalian target of rapamycin complex 1 (mTORC1) signaling have marked effects on the placental glucose transporter isoform-3, which may be involved in the pathophysiology of abnormal fetal growth
Summary
Inadequate nutrient supply from the mother to the fetus leads to abnormal intrauterine fetal growth, which may increase the risk for health problems, including obesity, diabetes and cardiovascular disease in both childhood and later life [1]. GLUT1 is a ubiquitous transporter found in all cells of the placenta; GLUT3 has a more restricted expression pattern, which suggests specialized functions for this protein. The GLUT3 isoform is expressed in cytotrophoblasts during early gestation but is localized primarily to the fetal vascular endothelium during late gestation [3,4]. This type of distribution pattern has important implications for glucose flux across the placenta. A glucose molecule must sequentially use both GLUT1 and GLUT3 to cross from maternal to fetal circulation [5], and the glucose supply to the fetus depends on the concentration gradient between mother and fetus [6,7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
