Adiponectin regulates nutrient transport in the placenta

描述(申请人提供)：肥胖是一种代价高昂且广泛传播的疾病，具有明显的代际传递。超过50%的女性进入怀孕阶段时超重或肥胖，而且更有可能生下大婴儿，这些婴儿在生命早期患肥胖症和代谢综合征的风险更高。母亲肥胖增加胎儿生长速度的机制尚不清楚，但增加胎盘的营养供应对于支持加速生长速度是必不可少的。我们的长期目标是了解人类妊娠期间胎盘营养物质转运的调节，以便设计预防和治疗胎儿生长异常的策略。此R03应用的目的是确定脂联素在调节胎盘营养物质运输中的作用。目前还没有关于脂联素在调节胎盘营养物质转运或胰岛素敏感性方面的作用的数据。胎盘产生脂联素，其受体定位于合体滋养细胞面向母体的表面。此外，妊娠大鼠注射脂联素后，葡萄糖转运蛋白3和脂蛋白脂酶(LPL)的mRNA表达也降低。我们的中心假设是，脂联素直接或通过影响胰岛素信号通路下调胎盘脂蛋白脂酶(LPL)、葡萄糖和氨基酸转运体的活性和表达。R03建议的基本原理是，了解脂联素在胎盘营养转运蛋白调节中的作用将使随后在R01水平上的机制研究成为可能。我们定义了两个特定的目标来验证中心假设：1)确定脂联素对胎盘营养物质转运蛋白的直接影响；2)确定脂联素对胰岛素刺激的胎盘营养物质转运蛋白的影响。我们的工作假设是，脂联素通过抑制AMP激活的蛋白激酶(AMPK)下调胎盘LPL、葡萄糖和氨基酸转运体的活性和表达，并通过减少胰岛素受体(IR)和胰岛素受体底物1(IRS-1)的酪氨酸磷酸化来抑制胰岛素刺激的胎盘A系统介导的氨基酸转运。这将通过将培养的原代滋养细胞在不同浓度的脂联素中孵育，在存在和不存在生理浓度的胰岛素的情况下进行测试，并测量脂联素、葡萄糖和氨基酸转运体的活性、基因和蛋白质表达(系统A和L)。这项研究具有创新性，因为我们提出了一个模型，在该模型中，脂联素降低了胰岛素敏感性，并下调了胎盘中的营养转运蛋白，而不是它在母体外周组织中的作用。如果这一模型被证明是正确的，它可以部分解释以母体脂联素低为特征的胎儿营养供应增加和胎儿过度生长的原因。拟议研究的预期结果是，它将产生的结果将为随后的机械化R01应用提供坚实的基础。拟议的研究与公共健康相关，因为它们解决了一种昂贵且广泛传播的疾病--肥胖症。肥胖妇女的婴儿较大，这些婴儿在生命早期患肥胖症和代谢综合征的风险增加。这项提案中的研究将提供初步数据，以解决母亲肥胖导致新生儿体重增加的机制。具体地说，我们将测试这一假设，即肥胖孕妇血液中低浓度的脂联素激素会增加胎盘将营养物质输送到胎儿的能力，从而刺激胎儿生长。这项研究可能会导致制定干预策略，以减轻肥胖女性怀孕期间的出生体重，这将降低下一代肥胖的易感性。

DESCRIPTION (provided by applicant): Obesity is a costly and wide-spread condition with a clear intergenerational transmission. More than 50% of women enter pregnancy overweight or obese and are more likely to deliver large babies who are at higher risk to develop obesity and metabolic syndrome early in life. The mechanisms whereby maternal adiposity increases fetal growth rates are unknown but an increased nutrient delivery across the placenta is essential to support the accelerated growth rate. Our long-term goal is to understand regulation of placental nutrient transport in human pregnancy in order to design strategies for prevention and therapy in pregnancies with altered fetal growth. The objective of this R03 application is to determine the role of adiponectin in regulating placental nutrient transport. No data exists on the role of adiponectin in modulating placental nutrient transport or insulin sensitivity. The placenta produces adiponectin and its receptors are localized in the maternal facing surface of the syncytiotrophoblast. Also, adiponectin infusion into pregnant rats caused a decrease in glucose transporter 3 and lipoprotein lipase (LPL) mRNA expression. Our central hypothesis is that adiponectin down-regulates the activity and expression of placental lipoprotein lipase (LPL) and glucose and amino acid transporters both directly and by affecting insulin signaling. The rationale for this R03 proposal is that, understanding the role of adiponectin in the regulation of placental nutrient transporters will enable subsequent mechanistic studies at the R01 level. We have defined two specific aims to validate the central hypothesis: 1) Determine the direct effects of adiponectin on placental nutrient transporters and 2) Identify effects of adiponectin on insulin-stimulated placental nutrient transport. Our working hypotheses are that adiponectin down-regulates the activity and expression of placental LPL, glucose and amino acid transporters by inhibition of AMP-activated protein kinase (AMPK) and inhibits insulin-stimulated placental System A mediated amino acid transport by decreasing tyrosine phosphorylation of the insulin receptor (IR) and insulin-receptor substrate 1 (IRS-1). This will be tested by incubating cultured primary trophboblast cells in varying concentrations of adiponectin, in the presence and absence of physiological concentrations of insulin, and measure the activity, gene and protein expression of LPL, glucose and amino acid transporters ( Systems A and L). This research is innovative because we propose a model where adiponectin decreases insulin sensitivity and down-regulates nutrient transporters in the placenta, in contrast to its' effects in maternal peripheral tissue. If this model proves to be correct, it could explain in part the increased nutrient delivery to the fetus and fetal overgrowth in pregnancies characterized by low maternal adiponectin. The expected outcome of the proposed research is that it will produce results that will provide a solid foundation for a subsequent, mechanistic R01 application. The proposed studies are relevant to public health because they address a costly and wide spread condition, obesity. Obese women have larger babies and these babies have an increased risk of developing obesity and metabolic syndrome early in life. The studies in this proposal will provide preliminary data to address the mechanisms whereby maternal obesity leads to increased birth weight. Specifically, we will test the hypothesis that low blood concentrations of the hormone adiponectin in obese pregnant women increase the capacity of the placenta to transport nutrients to the fetus, thereby stimulating fetal growth. This research may lead to the development of intervention strategies to reduce birth weight in pregnancies of obese women, which will reduce the susceptibility to obesity in the next generation.