Division of Neonatology and Developmental Biology, Neonatal Research Center, Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095-1752, USA.
Endocrinology. 2012 Aug;153(8):3995-4007. doi: 10.1210/en.2011-1973. Epub 2012 Jun 14.
Calorie restriction (CR) decreased placenta and fetal weights in wild-type (wt) and glucose transporter (Glut) 3 heterozygous null (glut3(+/-)) mice. Because placental nutrient transport is a primary energy determinant of placentofetal growth, we examined key transport systems. Maternal CR reduced intra- and transplacental glucose and leucine transport but enhanced system A amino acid transport in wt mice. These transport perturbations were accompanied by reduced placental Glut3 and leucine amino acid transporter (LAT) family member 2, no change in Glut1 and LAT family member 1, but increased sodium coupled neutral amino acid transporter (SNAT) and SNAT2 expression. We also noted decreased total and active phosphorylated forms of mammalian target of rapamycin, which is the intracellular nutrient sensor, the downstream total P70S6 kinase, and pS6 ribosomal protein with no change in total and phosphorylated 4E-binding protein 1. To determine the role of placental Glut3 in mediating CR-induced placental transport changes, we next investigated the effect of gestational CR in glut3(+/-) mice. In glut3(+/-) mice, a key role of placental Glut3 in mediating transplacental and intraplacental glucose transport was established. In addition, reduced Glut3 results in a compensatory increase of leucine and system A transplacental transport. On the other hand, diminished Glut3-mediated intraplacental glucose transport reduced leucine transport and mammalian target of rapamycin and preserved LAT and enhancing SNAT. CR in glut3(+/-) mice further reduced transplacental glucose transport and enhanced system A amino acid transport, although the increased leucine transport was lost. In addition, increased Glut3 was seen and preserved Glut1, LAT, and SNAT. These placental changes collectively protect survival of wt and glut3(+/-) fetuses against maternal CR-imposed reduction of macromolecular nutrients.
热量限制（CR）降低了野生型（wt）和葡萄糖转运体（Glut）3 杂合缺失（glut3(+/-)）小鼠的胎盘和胎儿体重。由于胎盘营养物质转运是胎盘胎儿生长的主要能量决定因素，我们检查了关键的转运系统。母体 CR 降低了 wt 小鼠的胎盘内和胎盘间葡萄糖和亮氨酸转运，但增强了系统 A 氨基酸转运。这些转运变化伴随着胎盘 Glut3 和亮氨酸氨基酸转运体（LAT）家族成员 2 的减少，Glut1 和 LAT 家族成员 1 没有变化，但钠离子偶联中性氨基酸转运体（SNAT）和 SNAT2 的表达增加。我们还注意到哺乳动物雷帕霉素靶蛋白（mTOR）的总磷酸化形式和下游的总 P70S6 激酶减少，而磷酸化 4E 结合蛋白 1 没有变化，mTOR 是细胞内营养传感器。为了确定胎盘 Glut3 在介导 CR 诱导的胎盘转运变化中的作用，我们接下来研究了妊娠 CR 在 glut3(+/-) 小鼠中的作用。在 glut3(+/-) 小鼠中，确立了胎盘 Glut3 在介导胎盘间和胎盘内葡萄糖转运中的关键作用。此外，减少 Glut3 导致亮氨酸和系统 A 胎盘间转运的代偿性增加。另一方面，减少的 Glut3 介导的胎盘内葡萄糖转运减少了亮氨酸转运和哺乳动物雷帕霉素，同时保留了 LAT 并增强了 SNAT。glut3(+/-) 小鼠中的 CR 进一步降低了胎盘间葡萄糖转运，并增强了系统 A 氨基酸转运，尽管增加的亮氨酸转运丢失了。此外，还观察到增加的 Glut3 并保留了 Glut1、LAT 和 SNAT。这些胎盘变化共同保护 wt 和 glut3(+/-) 胎儿免受母体 CR 施加的大分子营养物质减少的影响。
