Fetal growth restriction (FGR) is a common complication of pregnancy and can have significant impact on obstetric and neonatal outcomes. Increasing evidence has shown that the inhibited mechanistic target of rapamycin (mTOR) signaling in placenta is associated with FGR. However, interpretation of existing research is limited due to inconsistent methodologies and varying understanding of the mechanism by which mTOR activity contributes to FGR. Hereby, we have demonstrated that different anatomic regions of human and mouse placentas exhibited different levels of mTOR activity in normal compared to FGR pregnancies. When using the rapamycin-induced FGR mouse model, we found that placentas of FGR pregnancies exhibited abnormal morphological changes and reduced mTOR activity in the decidual-junctional layer. Using transcriptomics and lipidomics, we revealed that lipid and energy metabolism was significantly disrupted in the placentas of FGR mice. Finally, we demonstrated that maternal physical exercise during gestation in our FGR mouse model was associated with increased fetal and placental weight as well as increased placental mTOR activity and lipid metabolism. Collectively, our data indicate that the inhibited placental mTOR signaling contributes to FGR with altered lipid metabolism in mouse placentas, and maternal exercise could be an effective method to reduce the occurrence of FGR or alleviate the adverse outcomes associated with FGR.

Graphical Abstract

1. a)

   Human and mouse placentas have different mTOR signaling activities in different anatomic regions in normal and FGR pregnancies.

2. b)

   Pregnant mice with FGR induced by rapamycin show smaller placentas, decreased mTOR activity in DJ layer of placenta and altered lipid metabolism.

3. c)

   Maternal exercise partially alleviates the abnormal outcomes of FGR model.

中文翻译：

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胎儿生长受限在小鼠胎盘的不同区域表现出多种 mTOR 信号传导，脂质代谢发生改变

胎儿生长受限（FGR）是一种常见的妊娠并发症，会对产科和新生儿结局产生重大影响。越来越多的证据表明，胎盘中雷帕霉素靶点 (mTOR) 信号传导受到抑制与 FGR 相关。然而，由于方法不一致以及对 mTOR 活性促进 FGR 机制的不同理解，对现有研究的解释受到限制。在此，我们证明，与 FGR 妊娠相比，人类和小鼠胎盘的不同解剖区域在正常妊娠时表现出不同水平的 mTOR 活性。当使用雷帕霉素诱导的FGR小鼠模型时，我们发现FGR妊娠的胎盘表现出异常的形态变化，并且蜕膜交界层的mTOR活性降低。利用转录组学和脂质组学，我们发现 FGR 小鼠胎盘中的脂质和能量代谢受到显着破坏。最后，我们证明，在 FGR 小鼠模型中，妊娠期间母亲的体育锻炼与胎儿和胎盘重量的增加以及胎盘 mTOR 活性和脂质代谢的增加有关。总的来说，我们的数据表明，受抑制的胎盘 mTOR 信号传导导致 FGR，并改变小鼠胎盘的脂质代谢，而母亲运动可能是减少 FGR 发生或减轻与 FGR 相关的不良后果的有效方法。

图形概要

1. A）

   在正常妊娠和 FGR 妊娠中，人类和小鼠胎盘在不同解剖区域具有不同的 mTOR 信号传导活性。

2. b)

   雷帕霉素诱导的 FGR 妊娠小鼠表现出胎盘变小、胎盘 DJ 层 mTOR 活性降低以及脂质代谢改变。

3. C）

   母亲运动部分缓解了FGR模型的异常结果。