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: 7623987
• 负责人: Theresa L Powell
• 金额: --
• 依托单位: UNIVERSITY OF CINCINNATI
• 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 2009-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623987
• 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疾病，具有明显的代际传递。超过50%的妇女在怀孕时超重或肥胖，更有可能分娩出大婴儿，这些婴儿在生命早期患肥胖症和代谢综合征的风险更高。母体肥胖增加胎儿生长速率的机制尚不清楚，但增加胎盘的营养输送对支持加速的生长速率至关重要。我们的长期目标是了解人类妊娠中胎盘营养转运的调节，以便设计预防和治疗胎儿生长改变的妊娠策略。R 03申请的目的是确定脂联素在调节胎盘营养转运中的作用。脂联素在调节胎盘营养转运或胰岛素敏感性方面的作用尚无数据。胎盘产生脂联素，脂联素受体定位于合体滋养层面向母体的表面。此外，脂联素输注到妊娠大鼠引起葡萄糖转运蛋白3和脂蛋白脂酶（LPL）mRNA表达的下降。我们的中心假设是，脂联素下调胎盘脂蛋白脂酶（LPL）和葡萄糖和氨基酸转运蛋白的活性和表达，直接或通过影响胰岛素信号。该R 03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随后的R 01水平的机制研究成为可能。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活化蛋白激酶（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。这将通过在存在和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原代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）。这项研究是创新性的，因为我们提出了一个模型，脂联素降低胰岛素敏感性和下调营养转运蛋白在胎盘中，与其在母体外周组织的影响。如果这一模型被证明是正确的，它可以部分解释增加营养输送到胎儿和胎儿过度生长的孕妇特点是低产妇脂联素。拟议研究的预期结果是，它将产生的结果将为后续的机械R 01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。本提案中的研究将提供初步数据，以解决产妇肥胖导致出生体重增加的机制。具体来说，我们将测试的假设，即低血中的激素脂联素在肥胖的孕妇增加胎盘的能力，运输营养物质给胎儿，从而刺激胎儿生长。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。