Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center San Antonio, Mail Code 7836, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
J Physiol. 2012 Mar 15;590(6):1495-509. doi: 10.1113/jphysiol.2011.226399. Epub 2012 Jan 30.
Maternal adiponectin levels are inversely correlated to birth weight, suggesting that maternal adiponectin limits fetal growth. We hypothesized that full-length adiponectin (fADN) infusion in pregnant mice down-regulates placental amino acid transporters and decreases fetal growth. Starting at embryonic day (E) 14.5, fADN (0.62 ± 0.02 μg (g body weight)(−1) day(−1), n = 7) or vehicle (control, n = 9) were infused in pregnant C57/BL6 mice by mini-osmotic pump. At E18.5, dams were killed and placental homogenates and trophoblast plasma membrane (TPM) vesicles were prepared. Infusion of fADN elevated maternal serum fADN by 4-fold and decreased fetal weights by 18%. Adiponectin receptor 2, but not adiponectin receptor 1, was expressed in TPM. fADN infusion decreased TPM System A (–56%, P < 0.001) and System L amino acid transporter activity (–50%, P < 0.03). TPM protein expression of SNAT1, 2 and 4 (System A amino acid transporter isoforms) and LAT1 and LAT2, but not CD98, (System L amino acid transporter isoforms) was down-regulated by fADN infusion. To identify possible mechanisms underlying these changes we determined the phosphorylation of proteins in signalling pathways known to regulate placental amino acid transporters. fADN decreased phosphorylation of insulin receptor substrate-1 (Tyr-608), Akt (Thr-308 and Ser-473), S6 kinase 1 (Thr-389), eukaryotic initiation factor 4E binding protein 1 (Thr-37/46 and Thr-70) and ribosomal protein S6 (Ser-235/236) and increased the phosphorylation of peroxisome proliferator-activated receptor α (PPARα) (Ser-21) in the placenta. These data suggest that maternal adiponectin decreases fetal growth by down-regulation of placental amino acid transporters, which limits fetal nutrient availability. This effect may be mediated by inhibition of insulin/IGF-I and mTOR signalling pathways, which are positive regulators of placental amino acid transporters. We have identified a novel physiological mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth.
母体脂联素水平与出生体重呈负相关，表明母体脂联素限制了胎儿的生长。我们假设在怀孕的小鼠中输注全长脂联素（fADN）会下调胎盘氨基酸转运体并降低胎儿生长。从胚胎期第 14.5 天（E14.5）开始，通过迷你渗透泵向怀孕的 C57/BL6 小鼠输注 fADN（0.62±0.02μg（体重 g）（-1）天（-1），n=7）或载体（对照组，n=9）。在 E18.5 天，杀死母鼠并制备胎盘匀浆和滋养层质膜（TPM）囊泡。fADN 输注使母体血清 fADN 增加 4 倍，使胎儿体重减轻 18%。脂联素受体 2（但不是脂联素受体 1）在 TPM 中表达。fADN 输注降低 TPM System A（-56%，P<0.001）和 System L 氨基酸转运体活性（-50%，P<0.03）。fADN 输注下调 TPM 中的 SNAT1、2 和 4（System A 氨基酸转运体同工型）和 LAT1 和 LAT2（但不是 CD98，System L 氨基酸转运体同工型）的蛋白表达。为了确定这些变化的潜在机制，我们确定了已知调节胎盘氨基酸转运体的信号通路中蛋白质的磷酸化。fADN 降低了胰岛素受体底物-1（Tyr-608）、Akt（Thr-308 和 Ser-473）、S6 激酶 1（Thr-389）、真核起始因子 4E 结合蛋白 1（Thr-37/46 和 Thr-70）和核糖体蛋白 S6（Ser-235/236）的磷酸化，同时增加了过氧化物酶体增殖物激活受体α（PPARα）（Ser-21）在胎盘组织中的磷酸化。这些数据表明，母体脂联素通过下调胎盘氨基酸转运体来降低胎儿生长，从而限制了胎儿的营养供应。这种作用可能是通过抑制胰岛素/IGF-I 和 mTOR 信号通路来介导的，这些信号通路是胎盘氨基酸转运体的正调节因子。我们已经确定了一种新的生理机制，即母体脂肪组织的内分泌功能影响胎儿生长。
