Prince Calais S, Maloyan Alina, Myatt Leslie
Center for Pregnancy and Newborn Research, Dept of Obstetrics and Gynecology, University of Texas Health Science Center San Antonio, TX, 78229, USA.
Center for Pregnancy and Newborn Research, Dept of Obstetrics and Gynecology, University of Texas Health Science Center San Antonio, TX, 78229, USA; Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, 97239, USA.
Placenta. 2017 Jan;49:55-63. doi: 10.1016/j.placenta.2016.11.010. Epub 2016 Nov 24.
Obesity is a major clinical problem in obstetrics being associated with adverse pregnancy outcomes and fetal programming. Brain derived neurotrophic factor (BDNF), a validated miR-210 target, is necessary for placental development, fetal growth, glucose metabolism, and energy homeostasis. Plasma BDNF levels are reduced in obese individuals; however, placental BDNF has yet to be studied in the context of maternal obesity. In this study, we investigated the effect of maternal obesity and sexual dimorphism on placental BDNF signaling.
BDNF signaling was measured in placentas from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI>30) women at term without medical complications that delivered via cesarean section without labor. MiRNA-210, BDNF mRNA, proBDNF, and mature BDNF were measured by RT - PCR, ELISA, and Western blot. Downstream signaling via TRKB (BDNF receptor) was measured using Western blot.
Maternal obesity was associated with increased miRNA-210 and decreased BDNF mRNA in placentas from female fetuses, and decreased proBDNF in placentas from male fetuses. We also identified decreased mature BDNF in placentas from male fetuses when compared to female fetuses. Mir-210 expression was negatively correlated with mature BDNF protein. TRKB phosphorylated at tyrosine 817, not tyrosine 515, was increased in placentas from obese women. Maternal obesity was associated with increased phosphorylation of MAPK p38 in placentas from male fetuses, but not phosphorylation of ERK p42/44.
BDNF regulation is complex and highly regulated. Pre-pregnancy/early maternal obesity adversely affects BDNF/TRKB signaling in the placenta in a sexually dimorphic manner. These data collectively suggest that induction of placental TRKB signaling could ameliorate the placental OB phenotype, thus improving perinatal outcome.
肥胖是产科的一个主要临床问题，与不良妊娠结局和胎儿编程有关。脑源性神经营养因子（BDNF）是一个经过验证的miR-210靶点，对胎盘发育、胎儿生长、葡萄糖代谢和能量稳态至关重要。肥胖个体的血浆BDNF水平降低；然而，胎盘BDNF在母体肥胖背景下尚未得到研究。在本研究中，我们调查了母体肥胖和性别二态性对胎盘BDNF信号传导的影响。
在足月时，对无医学并发症、未经产通过剖宫产分娩的瘦女性（孕前BMI<25）和肥胖女性（孕前BMI >30）的胎盘进行BDNF信号传导检测。通过RT-PCR、ELISA和蛋白质印迹法检测miRNA-210、BDNF mRNA、前体BDNF和成熟BDNF。使用蛋白质印迹法检测通过TRKB（BDNF受体）的下游信号传导。
母体肥胖与女性胎儿胎盘miRNA-210增加和BDNF mRNA减少以及男性胎儿胎盘前体BDNF减少有关。与女性胎儿相比，我们还发现男性胎儿胎盘成熟BDNF减少。Mir-210表达与成熟BDNF蛋白呈负相关。肥胖女性胎盘酪氨酸817而非酪氨酸515磷酸化的TRKB增加。母体肥胖与男性胎儿胎盘MAPK p38磷酸化增加有关，但与ERK p42/44磷酸化无关。
BDNF调节复杂且受到高度调控。孕前/孕早期母体肥胖以性别二态性方式对胎盘中的BDNF/TRKB信号传导产生不利影响。这些数据共同表明，诱导胎盘TRKB信号传导可改善胎盘肥胖表型，从而改善围产期结局。
