Adiponectin regulates nutrient transport in the placenta

描述（由申请人提供）：肥胖是一种代价高昂且普遍存在的疾病，具有明显的代际遗传。超过50%的妇女在怀孕时超重或肥胖，更有可能生下体型较大的婴儿，这些婴儿在生命早期患肥胖症和代谢综合征的风险更高。母体肥胖增加胎儿生长速率的机制尚不清楚，但通过胎盘增加的营养输送对支持加速生长速率至关重要。我们的长期目标是了解人类妊娠期间胎盘营养转运的调节，以便设计预防和治疗妊娠胎儿生长改变的策略。本R03应用的目的是确定脂联素在调节胎盘营养转运中的作用。尚无关于脂联素在调节胎盘营养转运或胰岛素敏感性中的作用的资料。胎盘产生脂联素，其受体位于合胞滋养细胞的母体表面。此外，脂联素输注妊娠大鼠导致葡萄糖转运蛋白3和脂蛋白脂肪酶（LPL） mRNA表达降低。我们的中心假设是脂联素直接或通过影响胰岛素信号传导下调胎盘脂蛋白脂肪酶（LPL）、葡萄糖和氨基酸转运蛋白的活性和表达。这一R03建议的基本原理是，了解脂联素在胎盘营养转运蛋白调控中的作用，将有助于在R01水平上进行后续的机制研究。我们确定了两个具体目标来验证中心假设：1)确定脂联素对胎盘营养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转运的影响。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蛋白的活性和表达，并通过降低胰岛素受体（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系统A介导的氨基酸转运。这将通过培养培养的原代滋养母细胞在不同浓度的脂联素、存在和不存在生理浓度的胰岛素中进行测试，并测量LPL、葡萄糖和氨基酸转运蛋白（系统A和L）的活性、基因和蛋白质表达。这项研究具有创新性，因为我们提出了一个模型，其中脂联素降低胰岛素敏感性并下调胎盘中的营养转运蛋白，而不是其在母体外周组织中的作用。如果这个模型被证明是正确的，那么它就可以部分地解释以母体低脂联素为特征的妊娠中胎儿营养输送增加和胎儿过度生长的现象。拟议研究的预期结果是，它将产生的结果将为后续的机械R01应用提供坚实的基础。拟议的研究与公共卫生有关，因为它们解决了一种昂贵且广泛传播的疾病——肥胖。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。本提案中的研究将为解决产妇肥胖导致出生体重增加的机制提供初步数据。具体来说，我们将验证肥胖孕妇血液中低浓度的激素脂联素会增加胎盘向胎儿输送营养物质的能力，从而刺激胎儿生长的假设。这项研究可能会导致干预策略的发展，以减少肥胖妇女怀孕时的出生体重，这将减少下一代对肥胖的易感性。

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.