Chronic maternal infusion of full-length adiponectin in pregnant mice down-regulates placental amino acid transporter activity and expression and decreases fetal growth
Chronic maternal infusion of full-length adiponectin in pregnant mice down-regulates placental amino acid transporter activity and expression and decreases fetal growth
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DOI：
10.1113/jphysiol.2011.226399
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发表时间：
2012-03-01
影响因子：
5.5
通讯作者：
Jansson, Thomas
中科院分区：
文献类型：
--
作者：
Rosario, Fredrick J.;Schumacher, Michael A.;Jansson, Thomas
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胎儿生长。我们假设怀孕小鼠输注全长脂联素 (fADN) 会下调胎盘氨基酸转运蛋白并降低胎儿生长。从胚胎天（E）14.5开始，通过微型渗透泵将fADN（0.62+/-0.02μg（体重）（-1）天（-1），n = 7）或载体（对照，n = 9）输注到怀孕的C57/BL6小鼠中。在E18.5，处死母鼠并制备胎盘匀浆和滋养层质膜（TPM）囊泡。输注 fADN 可使母体血清 fADN 升高 4 倍，并使胎儿体重降低 18%。 TPM 中表达脂联素受体 2，但不表达脂联素受体 1。 fADN输注降低了TPM系统A（-56%，P < 0.001）和系统L氨基酸转运蛋白活性（-50%，P < 0.03）。 fADN 输注下调了 SNAT1、2 和 4（系统 A 氨基酸转运蛋白同工型）以及 LAT1 和 LAT2 的 TPM 蛋白表达，但 CD98（系统 L 氨基酸转运蛋白同工型）的 TPM 蛋白表达没有下调。为了确定这些变化背后的可能机制，我们确定了已知调节胎盘氨基酸转运蛋白的信号通路中蛋白质的磷酸化。 fADN 降低胰岛素受体底物 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，并增加过氧化物酶体的磷酸化胎盘中的增殖剂激活受体 a (PPARa) (Ser-21)。这些数据表明，母体脂联素通过下调胎盘氨基酸转运蛋白来降低胎儿生长，从而限制胎儿营养的利用。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蛋白的正调节因子。我们已经确定了一种新的生理机制，母体脂肪组织的内分泌功能可以影响胎儿的生长。
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 mu g (gbodyweight)(-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 a (PPARa) (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.