The emerging role of mTORC1 signaling in placental nutrient-sensing
Introduction
In single cell organisms, such as yeast, nutrient-sensing signaling pathways up-regulate nutrient uptake and metabolism in response to increased levels of intracellular nutrients or their metabolites. Conversely, when subjected to nutrient deprivation these nutrient sensors cause down-regulation of membrane nutrient transporter expression and inhibition of cell metabolism, providing a direct link between nutrient availability and cell growth [1], [2]. In contrast, in mammalian cells nutrient uptake, metabolism and growth have long been believed to be controlled primarily by growth factors. However, in the past 10–15 years it has become increasingly clear that mammalian cells have an array of additional nutrient-sensing signaling pathways, such as AMP-activated protein kinase (AMPK), mammalian target of rapamycin complex 1 (mTORC1) and the hexosamine signaling pathway, which regulate cell metabolism in response to altered nutrient levels. In general, these nutrient sensors promote an anabolic phenotype when nutrient availability is abundant and a catabolic phenotype in times of nutrient deprivation. Mammalian nutrient-sensing pathways operate both independently of, and in concert with, growth factor signaling. While these nutrient-sensing signaling pathways are relatively well characterized, in many cases the molecular identity of the actual sensor remains elusive [1].
In the human term placenta only two cell layers separate the maternal and the fetal circulations, the syncytiotrophoblast cells, which are in direct contact with maternal blood, and the fetal capillary endothelium. The syncytiotrophoblast, the transporting epithelium and the primary endocrine cell of the human placenta, plays a critical role in determining fetal growth and development, mediated by a multitude of functions including nutrient transport to the fetus and orchestrating the maternal physiological adaptation to pregnancy. Thus, nutrient-sensing in the trophoblast is unique in that it not only directly regulates trophoblast metabolism and growth but may also influence the development and long-term health of the fetus. In this review, we initially provide a brief overview of trophoblast signaling pathways, which may function as placental nutrient sensors. Subsequently, we focus on mTORC1 because there is significant evidence for a role for this signaling pathway in placental nutrient-sensing. First, we argue that mTORC1 is regulated by a large number of upstream signals, which are likely to be altered in association to common pregnancy complications. Second, we discuss the evidence that mTORC1 is a powerful positive regulator of key placental nutrient transporters. Third, we review data demonstrating that placental mTORC1 activity changes in relation to maternal nutrient availability. Finally, we discuss exciting new data on the molecular mechanisms of AA-sensing, its impact on the mTORC1 signaling pathway and the possibility that placental mTORC1 signaling directly influences fetal metabolism.
Section snippets
Placental nutrient sensors
Because an extensive discussion of all potential placental nutrient sensors is beyond the scope of this brief review, we will focus on some important examples. In most instances, the activity of nutrient-sensing pathways in the placenta has been assessed in placental homogenates whereas studies in cultured trophoblast cells have so far been uncommon. The amino acid response (AAR) signal transduction pathway is activated by limitation or imbalance of essential amino acids (EAAs) [3]. In these
mTORC1 signaling
mTOR is a ubiquitously expressed serine/threonine kinase that exists as two complexes with distinct regulation and function [16], [17]. One key difference between the two complexes is the association of mTOR with the accessory protein raptor in mTOR Complex 1 (mTORC1) and with rictor in mTORC2. mTORC2 phosphorylates Akt at Serine-473, protein kinase C α (PKCα) and serum/glucocorticoid regulated kinase 1 (SGK1) and is not believed to be directly involved in nutrient-sensing [18], [19]. In
Evidence supporting a role for mTORC1 in placental nutrient-sensing
mTOR is highly expressed in the syncytiotrophoblast of the human placenta [34] and mTORC1 in cultured primary human trophoblast cells is regulated by glucose and AA concentrations as well as by growth factor signaling [35]. Placental insulin/IGF-I signaling is inhibited in IUGR [5], [12], [13] and the IUGR fetus is often hypoxemic and hypoglycaemic and has low circulating levels of EAAs [36], [37], consistent with the possibility that nutrient and oxygen levels are also low in the trophoblast.
The nature of the intracellular amino acid sensing mechanism and the role of PAT1
The level of extracellular AAs is one of the key inputs affecting mTORC1 activity. mTORC1 is particularly sensitive to changes in the levels of specific AAs, such as leucine [48]. Indeed the leucine-bound leucyl-tRNA synthetase has recently been shown to act as a leucine sensor for mTORC1 activation, although as discussed below, this does not provide the only mechanism by which AAs are sensed and may act more as a permissive signal under normal cellular condition [49], [50]. Our understanding
Remote control of fetal metabolism by placental mTOR?
Trophoblast mTOR signaling can influence fetal growth and metabolism indirectly by regulating trophoblast AA transporter activity [34], [40]. Inhibition of the TOR signaling pathway in the fat body of Drosophila influences whole body growth mediated by the release of a humoral factor that regulates the secretion of insulin-like peptides from the brain [60]. By analogy to the role of TOR in the fat body of Drosophila, we hypothesized that human placental mTOR signaling regulates the release of a
Conclusions and future perspectives
We have reviewed evidence implicating mTORC1 signaling as an important placental nutrient sensor. First, placental insulin/IGF-I signaling and levels of oxygen, glucose and AAs are altered in pregnancy complications such as IUGR, and all these factors are well-established upstream regulators of mTORC1. Second, mTORC1 is a positive regulator of the placental AA transporters, suggesting that trophoblast mTORC1 modulates AA transfer across the placenta. Third, placental mTORC1 is regulated in
Conflict of interest statement
None of the authors have any actual or potential conflict of interest to disclose, including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work.
Acknowledgments
This work was supported by NIH grant HD 068370 (to TJ) and by Cancer Research UK (CR-UK) grant number C38302/A12278, through the Oxford Cancer Research Centre Development Fund (to DCIG). We thank John Morris for helpful comments on the manuscript.
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