Activation of Placental mTOR Signaling and Amino Acid Transporters in Obese Women Giving Birth to Large Babies
Activation of Placental mTOR Signaling and Amino Acid Transporters in Obese Women Giving Birth to Large Babies
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DOI：
10.1210/jc.2012-2667
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发表时间：
2013-01-01
影响因子：
5.8
通讯作者：
Powell, Theresa L.
中科院分区：
文献类型：
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作者：
Jansson, Nina;Rosario, Fredrick J.;Powell, Theresa L.
背景：肥胖妇女的婴儿出生时通常很大，这与围产期并发症和以后生活中的代谢综合征有关。母亲肥胖与胎儿过度生长之间的联系机制在很大程度上是未知的。目的：我们检验了一个假设，即肥胖妇女的大婴儿胎盘胰岛素/IGF-I和哺乳动物雷帕霉素靶蛋白（mTOR）信号被激活，氨基酸转运蛋白活性增加。在大学医院和学术生物医学中心前瞻性招募孕妇收集胎盘组织。参会人员：23名瑞典孕妇参加了这项研究，她们的头三个月体重指数在18. 5到44. 9 kg/m2之间，并且怀孕没有并发症。干预措施：主要结果测量：我们确定了胎盘胰岛素/IGF-I、AMPK和mTOR信号通路中关键信号分子（包括Akt、IRS-1、S6 K1、4 EBP-1、RPS 6和AMPK）的磷酸化。结果：出生体重（3025-4235 g）与母体体重指数（BMI）呈正相关（P < 0.05），出生体重与母体BMI呈正相关（P < 0.05）。胎盘胰岛素/IGF-I和mTOR信号活性与出生体重呈正相关（P < 0.001），而AMPK磷酸化与出生体重呈负相关（P < 0.05）。微绒毛质膜系统A（而非系统L）、系统A亚型SNAT 2的活性和蛋白表达与出生体重呈正相关（P < 0.001）。结论：胎盘氨基酸转运蛋白亚型表达上调可能与母亲肥胖导致胎儿过度生长有关。这种作用可能是通过激活胰岛素/IGF-I和mTOR信号通路介导的，它们是胎盘氨基酸转运蛋白的正调节因子。（J Clin Endocrinol Metab 98：105-113，2013）
Context: Babies of obese women are often large at birth, which is associated with perinatal complications and metabolic syndrome later in life. The mechanisms linking maternal obesity to fetal overgrowth are largely unknown.Objective: We tested the hypothesis that placental insulin/IGF-I and mammalian target of rapamycin (mTOR) signaling is activated and amino acid transporter activity is increased in large babies of obese women.Design and Setting: Pregnant women were recruited prospectively for collection of placental tissue at a university hospital and academic biomedical center.Patients or Other Participants: Twenty- three Swedish pregnant women with first trimester body mass index ranging from 18.5 to 44.9 kg/m(2) and with uncomplicated pregnancies participated in the study. Interventions: There were no interventions.Main Outcome Measures: We determined the phosphorylation of key signaling molecules (including Akt, IRS-1, S6K1, 4EBP-1, RPS6, and AMPK) in the placental insulin/IGF-I, AMPK, and mTOR signaling pathways. The activity and protein expression of the amino acid transporter systems A and L were measured in syncytiotrophoblast microvillous plasma membranes.Results: Birth weights (range, 3025-4235 g) were positively correlated to maternal body mass index (P < 0.05). The activity of placental insulin/IGF-I and mTOR signaling was positively correlated (P < 0.001), whereas AMPK phosphorylation was inversely (P < 0.05) correlated to birth weight. Microvillous plasma membrane system A, but not system L, activity and protein expression of the system A isoform SNAT2 were positively correlated to birth weight (P < 0.001).Conclusions: Up-regulation of specific placental amino acid transporter isoforms may contribute to fetal overgrowth in maternal obesity. This effect may be mediated by activation of insulin/IGF-I and mTOR signaling pathways, which are positive regulators of placental amino acid transporters. (J Clin Endocrinol Metab 98: 105-113, 2013)