von Versen-Höynck F, Rajakumar A, Parrott M S, Powers R W
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, USA.
Placenta. 2009 Apr;30(4):361-7. doi: 10.1016/j.placenta.2009.01.004. Epub 2009 Feb 8.
Amino acids are important nutrients during fetal development, and the activity of placental amino acid transporters is crucial in the regulation of fetal growth. Leptin, an adipocyte- and placenta-derived hormone, has been proposed to act as a peripheral signal in reproduction in humans. Leptin is elevated during pregnancy and elevated further in pathologic pregnancies such as preeclampsia. However, the role of leptin in placental function has not been fully elucidated. We hypothesize that leptin plays a role in the regulation of placental amino acid transport by activation of the JAK-STAT pathway.
Placental amino acid transport, specifically system A transport was studied in placental villous fragments using the amino acid analog, methylaminoisobutyric acid (MeAIB). Specific inhibitors of the JAK-STAT signal transduction pathway were used to further elucidate their role in leptin-mediated effects on amino acid transport activity. Western blotting was performed to identify STAT3 phosphorylation as a measure of leptin receptor activation.
Leptin significantly increased system A amino acid transporter activity by 22-42% after 1h of incubation. Leptin activated JAK-STAT signaling pathway as evidenced by STAT3 phosphorylation, and inhibition of STAT3 or JAK2 resulted in 36-45% reduction in system A amino acid transporter activity. Furthermore, blocking endogenously produced leptin also decreased system A transport by 45% comparable to STAT3 inhibition.
These data demonstrate that leptin stimulates system A by JAK-STAT dependent pathway in placental villous fragments. Our findings support the autocrine/paracrine role of leptin in regulating amino acid transport in the human placenta.
氨基酸是胎儿发育过程中的重要营养素，胎盘氨基酸转运体的活性对于胎儿生长的调节至关重要。瘦素是一种由脂肪细胞和胎盘产生的激素，被认为是人类生殖中的一种外周信号。孕期瘦素水平升高，在子痫前期等病理妊娠中进一步升高。然而，瘦素在胎盘功能中的作用尚未完全阐明。我们假设瘦素通过激活JAK-STAT途径在胎盘氨基酸转运调节中发挥作用。
使用氨基酸类似物甲基氨基异丁酸（MeAIB），在胎盘绒毛片段中研究胎盘氨基酸转运，特别是A系统转运。使用JAK-STAT信号转导途径的特异性抑制剂进一步阐明它们在瘦素介导的氨基酸转运活性影响中的作用。进行蛋白质印迹以鉴定STAT3磷酸化作为瘦素受体激活的指标。
孵育1小时后，瘦素使A系统氨基酸转运体活性显著增加22%-42%。瘦素激活了JAK-STAT信号通路，表现为STAT3磷酸化，抑制STAT3或JAK2导致A系统氨基酸转运体活性降低36%-45%。此外，阻断内源性产生的瘦素也使A系统转运降低45%，与STAT3抑制相当。
这些数据表明，瘦素通过JAK-STAT依赖途径刺激胎盘绒毛片段中的A系统。我们的研究结果支持瘦素在调节人胎盘氨基酸转运中的自分泌/旁分泌作用。
