Placental adiponectin signaling and fetal programming in maternal obesity

超过60%的美国妇女现在进入怀孕超重或肥胖，这增加了风险， 婴儿在童年和以后的生活中患上肥胖症、糖尿病和心血管疾病。但 母体肥胖的子宫内环境与胎儿后期疾病规划之间的联系机制 对这些问题的了解仍然很少，这是制定具体干预措施的主要障碍 战略布局在肥胖孕妇和我们的小鼠模型中，脂联素的循环水平降低 母亲肥胖症。我们以前曾报道过脂联素，与其众所周知的胰岛素相反， 在骨骼肌和肝脏中的致敏作用，抑制胎盘胰岛素和mTOR信号传导以及氨基酸 运输这种作用是通过滋养层细胞的过氧化物酶体增殖物激活受体介导的， 合成导致IRS-1的抑制。值得注意的是，在我们新的母体肥胖模型中， 与人类状况的广泛相似性（母体瘦素水平升高，葡萄糖耐受不良， 胎盘胰岛素和mTOR信号传导的激活，胎盘营养转运增加和胎儿过度生长）， 脂联素循环水平恢复正常可完全预防胎盘功能障碍， 高血糖和过度生长。我们的研究结果表明，低循环脂联素在母亲肥胖， 与胎盘营养转运和胎儿生长增加有关。但无论 妊娠期母体脂联素水平正常化可减轻长期不利的代谢， 子宫内暴露于母体肥胖对后代的心血管后果尚不清楚。我们 核心假设是妊娠晚期补充脂联素可以预防妊娠晚期的发展， 代谢和心血管疾病的后代在回应母亲肥胖，这种影响是 由胎盘中的脂联素受体2（AdipoR 2）介导。这一假设得到了令人信服的支持， 初步数据包括肥胖母鼠的3个月大雄性后代（1）发育的证明， 肥胖、糖耐量异常、高脂血症和脂肪肝;（2）具有胎儿心脏基因的上调， 心脏胰岛素和mTOR信号传导的激活和左心室舒张功能障碍，以及（3）这些 在怀孕期间补充母体脂联素可以防止发育程序性变化。 使用迷你渗透泵，我们将补充脂联素的最后四天怀孕瘦和肥胖 母鼠，有或没有滋养层特异性敲低AdipoR 2，并研究3岁时的雄性和雌性后代 和6个月大，以解决我们的假设在三个具体目标：确定脂联素的影响， 在肥胖母鼠中补充对后代代谢（目标1）和心血管功能（目标2）的影响， 确定胎盘脂联素受体在母体肥胖胎儿编程中的机制作用 (Aim 3）。这项工作将对实地产生重大和持续的影响，因为它将导致更好的 了解胎盘在介导子宫内编程中的机制作用，并可能导致新的 具体的干预策略，以减轻母亲肥胖对后代的不良影响。

Over 60% of American women now enter pregnancy either overweight or obese, which increases the risk for the infant to develop obesity, diabetes and cardiovascular disease in childhood and later in life. However, the mechanisms linking the in utero environment in maternal obesity to programming of the fetus for later disease remain poorly understood, which constitutes a major roadblock for the development of specific intervention strategies. Circulating levels of adiponectin are decreased in obese pregnant women and in our mouse model of maternal obesity. We have previously reported that adiponectin, in contrast to its well-known insulin- sensitizing effects in skeletal muscle and liver, inhibits placental insulin and mTOR signaling and amino acid transport. This effect is mediated by activation of trophoblast PPARsignaling, which increases ceramide synthesis resulting in inhibition of IRS-1. Remarkably, in our novel model of maternal obesity, which shows extensive similarities with the human condition (elevated levels of maternal leptin, glucose intolerance, activation of placental insulin and mTOR signaling, increased placental nutrient transport and fetal overgrowth), restoration of normal circulating levels of adiponectin completely prevented placental dysfunction, fetal hyperglycemia and overgrowth. Our findings demonstrate that low circulating adiponectin in maternal obesity is mechanistically linked to increased placental nutrient transport and fetal growth. However, whether normalization of maternal adiponectin levels in pregnancy attenuates the long-term adverse metabolic and cardiovascular consequences of intrauterine exposure to maternal obesity in the offspring is unknown. Our central hypothesis is that adiponectin supplementation in late pregnancy prevents the development of metabolic and cardiovascular disease in the offspring in response to maternal obesity and that this effect is mediated by adiponectin receptor 2 (AdipoR2) in the placenta. This hypothesis is supported by compelling preliminary data including the demonstration that 3-month old male offspring of obese dams (1) develop obesity, glucose intolerance, hypertriglyceridemia and fatty liver; (2) have up-regulation of fetal cardiac genes, activation of cardiac insulin and mTOR signaling and left ventricular diastolic dysfunction and (3) these developmentally programmed changes are prevented by maternal adiponectin supplementation in pregnancy. Using mini-osmotic pumps, we will supplement adiponectin the last four days of pregnancy to lean and obese dams, with or without trophoblast-specific knock down of AdipoR2, and study male and female offspring at 3 and 6 months of age to address our hypothesis in three specific aims: Determine the effect of adiponectin supplementation in obese dams on offspring metabolism (Aim 1) and cardiovascular function (Aim 2) and to determine the mechanistic role of placental adiponectin receptors in fetal programming in maternal obesity (Aim 3). This work will have a significant and sustained impact on the field because it will lead to a better understanding of the mechanistic role of the placenta in mediating in utero programming and may lead to novel specific intervention strategies to alleviate the adverse effects of maternal obesity on the offspring.