Adiponectin regulates nutrient transport in the placenta

脂联素调节胎盘中的营养物质运输

• 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
• 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' -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

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）：肥胖是一种昂贵且广泛的条件，具有清晰的代际传播。超过50％的妇女超重或肥胖，更有可能分娩大型婴儿，这些婴儿在生命的早期就会患上肥胖和代谢综合症的风险更高。孕产妇肥胖增加胎儿生长率的机制尚不清楚，但是在整个胎盘上增加的营养递送对于支持加速生长速率至关重要。我们的长期目标是了解对人类怀孕中胎盘营养的运输的调节，以设计胎儿生长改变的妊娠预防和治疗策略。该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。没有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。胎盘会产生脂联素，其受体位于合成细胞细胞的母体面部表面中。同样，脂联素输注对孕妇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下调了胎盘脂蛋白脂肪酶（LPL）和葡萄糖和氨基酸转运蛋白的活性和表达，并通过影响胰岛素信号传导。该R03提案的理由是，了解脂联素在调节胎盘营养转运蛋白中的作用将使随后的机械研究在R01水平上进行。我们定义了两个特定的目的旨在验证中心假设：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）来下调胎盘LPL，葡萄糖和氨基酸转运蛋白的活性和表达（IRS-1）。这将通过在存在和不存在胰岛素的生理浓度的情况下以不同浓度的脂联素孵育的原代滋养剂细胞来测试，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，因为我们提出了一个模型，其中脂联素会降低胰岛素的敏感性并下调胎盘中的营养转运蛋白，与其在母体外周组织中的作用相反。如果该模型被证明是正确的，则可以部分解释以低母体脂联素为特征的妊娠中胎儿和胎儿过度生长的养分增加。拟议的研究的预期结果是，它将产生结果，为随后的机械R01应用提供坚实的基础。拟议的研究与公共卫生有关，因为它们涉及肥胖的昂贵且广泛的蔓延状况。肥胖的妇女有更大的婴儿，这些婴儿在生命的早期就会增加肥胖和代谢综合症的风险。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。具体而言，我们将检验以下假设：肥胖孕妇中血液脂联素的低血液浓度增加了胎盘将养分运送到胎儿的能力，从而刺激了胎儿的生长。这项研究可能导致制定干预策略，以减轻肥胖女性怀孕的出生体重，这将降低下一代肥胖症的易感性。