Adiponectin regulates nutrient transport in the placenta

脂联素调节胎盘中的营养物质运输

基本信息

批准号：
8064455
负责人：
Theresa L Powell
金额：
$ 7.42万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064455
关键词：
5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Abbreviations Address Adipocytes Affect Amino Acid Transport System A Amino Acid Transporter Amino Acids Birth Weight Blood Cells Childhood Data Development Fatty Acids Fetal Growth Fetus Figs - dietary Foundations Functional disorder Gene Proteins Gestational Diabetes Glucose Glucose Transporter Goals Growth High birth weight infant Hormones Human Incubated Infusion procedures Inositol Insulin Insulin Receptor Intervention Lead Life Link Lipids Literature Measures Mediating Metabolic syndrome Modeling Morbidity - disease rate Muscle Nutrient Obesity Outcome Overweight Perinatal Peripheral Phosphorylation Phosphotransferases Physiological Placenta Plasma Predisposition Pregnancy Pregnancy Complications Pregnancy in Diabetics Pregnant Women Prevention therapy Public Health Rattus Regulation Reporting Research Risk Role SLC2A1 gene Skeletal Muscle Solid Surface Syncytiotrophoblast System Testing Tissues Tyrosine Phosphorylation Woman Work adiponectin base design fetal glucose transport high risk innovation insulin receptor substrate 1 protein insulin sensitivity insulin signaling intergenerational lipoprotein lipase mRNA Expression next generation novel strategies pregnant protein expression receptor transmission process trophoblast uptake

项目摘要

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.

描述（由申请人提供）：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性。超过 50% 的女性在怀孕时体重超重或肥胖，并且更有可能生下较大的婴儿，而这些婴儿在生命早期患肥胖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，但增加胎盘营养输送对于支持加速生长速度至关重要。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，以便设计针对胎儿生长改变的妊娠的预防和治疗策略。 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。目前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数据。胎盘产生脂联素，其受体位于合体滋养层面向母体的表面。此外，向怀孕大鼠输注脂联素会导致葡萄糖转运蛋白 3 和脂蛋白脂肪酶 (LPL) mRNA 表达减少。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) 以及葡萄糖和氨基酸转运蛋白的活性和表达。 R03 提案的基本原理是，了解脂联素在胎盘营养转运蛋白调节中的作用将使后续 R01 水平的机制研究成为可能。我们定义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。胰岛素受体 (IR) 和胰岛素受体底物 1 (IRS-1)。这将通过在存在或不存在生理浓度的胰岛素的情况下在不同浓度的脂联素中孵育培养的初级滋养层细胞进行测试，并测量 LPL、葡萄糖和氨基酸转运蛋白的活性、基因和蛋白质表达（系统 A 和 L）。这项研究具有创新性，因为我们提出了一种模型，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，与其在母体周围组织中的作用相反。如果这个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妊娠期间向胎儿输送的营养增加和胎儿过度生长。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相关，因为它们解决了一种代价高昂且广泛传播的疾病——肥胖。肥胖女性会生出较大的婴儿，而这些婴儿在生命早期患肥胖和代谢综合征的风险会增加。该提案中的研究将提供初步数据，以解决孕产妇肥胖导致出生体重增加的机制。具体来说，我们将检验以下假设：肥胖孕妇血液中脂联素激素浓度较低，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。这项研究可能会导致制定干预策略，以降低肥胖女性怀孕期间的出生体重，从而降低下一代对肥胖的易感性。