Adiponectin, placental nutrient transport and fetal growth

脂联素、胎盘营养转运和胎儿生长

• 批准号: 8598487
• 负责人: Thomas Jansson
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-25 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598487
• 关键词: Adaptor Signaling Protein; Address; Adipose tissue; American; Amino Acid Transporter; Amino Acids; Binding; Cardiovascular Diseases; Cell membrane; Cells; Child; Childhood; Chronic; Data; Development; Diabetes Mellitus; Diet; Down-Regulation; Embryo; Endocrine; Endocrine Glands; Fatty acid glycerol esters; Fetal Growth; Fetus; Gene Expression; Gestational Age; Gestational Diabetes; Glucose; Glucose Transporter; Hormones; Human; Implant; Incubated; Infant; Infertility; Infusion procedures; Insulin; Insulin Signaling Pathway; Insulin-Like Growth Factor I; Intervention; Knowledge; Lead; Leucine Zippers; Life; Link; Literature; Measures; Mediating; Metabolic syndrome; Metabolism; Modeling; Mothers; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Overweight; PH Domain; PTB Domain; Perinatal; Peripheral; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Physiological; Placenta; Pregnancy; Pregnant Women; Protein Isoforms; Proteins; Pump; Rattus; Replacement Therapy; Reporting; Reproduction; Research; Risk; Role; Serine; Signal Pathway; Signal Transduction; Small Interfering RNA; Tissues; Up-Regulation; Weight; Woman; adiponectin; base; fetal; in vivo; innovation; insulin sensitivity; insulin signaling; knock-down; lipoprotein lipase; mRNA Expression; novel; pregnant; protein expression; public health relevance; receptor; research study; response; transmission process; trophoblast; uptake

DESCRIPTION (provided by applicant): Obesity and gestational diabetes (GDM) increase the risk of fetal overgrowth, which is associated with perinatal complications and development of metabolic syndrome in childhood or later in life. Maternal adiponectin (ADN) levels are reduced and placental nutrient transporters are up regulated in these pregnancies, however the effects of ADN on placental function are largely unknown. Our preliminary studies show that ADN regulates placental amino acid (AA) transporters. The objective of this proposal is to determine the mechanisms by which ADN regulates placental nutrient transporters and influences fetal growth. The central hypothesis is that ADN binds to the AdipoR2 in the placenta and, mediated by APPL1, activates p38MAPK and PPAR-1, which inhibit the insulin/IGF-I signaling pathway resulting in a down-regulation of nutrient transport and reduced fetal growth. Our hypothesis has been formulated on the basis of strong preliminary data demonstrating that ADN (i) inhibits insulin-stimulated AA transport, (ii) activates PPAR-1, (iii) abolishes insulin-stimulated Akt and IRS-1 phosphorylation in cultured trophoblast cells, and (iv) chronic infusions of ADN in pregnant mice inhibits the placental insulin signaling pathway and reduces fetal size. We propose three Specific Aims: (1) Determine the effects of ADN on placental nutrient transport and identify the receptors and APPL isoforms mediating these effects. We will incubate cultured human primary trophoblast cells (with and without siRNA knock-down of AdipoR1 & 2 and APPL 1 & 2) in physiological concentrations of ADN and/or insulin and study the activity, gene and protein expression of transporters for glucose and amino acids. (2) Identify the intracellular signaling pathways involved in mediating the effects of ADN on placental nutrient transporters. We will incubate cultured human primary trophoblast cells in ADN and/or insulin and study the phosphorylation and expression of p38MAPK, PPAR-1, IRS-1, and Akt. In cause-and-effect experiments we will transfect cultured primary human trophoblast cells with siRNA targeting key components of these signaling pathways and re-examine the effects of ADN on insulin signaling and nutrient uptake, and (3) Establish the effects of maternal ADN on placental insulin signaling, nutrient transport and fetal growth in vivo. We will infuse ADN during the last week of gestation in mice by mini- osmotic pumps. At embryonic day 18.5 we will study maternal metabolism, placental nutrient transport in vivo, placental nutrient transporter expression and placental p38MAPK, PPAR-1, IRS-1 and Akt signaling. This research is innovative because we propose a novel model where ADN, in contrast to its action in maternal peripheral tissues, causes decreased insulin sensitivity in the placenta. Furthermore, this proposal will lead to the discovery of a novel mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth. This is significant because this model predicts that low maternal ADN in obesity and GDM increase placental insulin sensitivity, which contributes to enhanced placental nutrient transport and fetal growth.

描述（由申请人提供）：肥胖和妊娠糖尿病（GDM）增加了胎儿过度生长的风险，这与儿童期或以后的生活中的围产期并发症和代谢综合征的发展有关。母体脂联素（ADN）水平降低，胎盘营养转运蛋白在这些妊娠中受到调节，但是ADN对胎盘功能的影响在很大程度上尚不清楚。我们的初步研究表明，ADN调节胎盘氨基酸（AA）转运蛋白。该提案的目的是确定ADN调节胎盘营养转运蛋白并影响胎儿生长的机制。中心假设是ADN与胎盘中的ADIPOR2结合，并由Appl1介导，激活了p38MAPK和PPAR-1，这抑制了胰岛素/IGF-I信号传导途径，从而导致营养转运的下调和胎儿生长降低。我们的假设是根据强大的初步数据提出的，表明ADN（I）抑制胰岛素刺激的AA转运，（ii）激活PPAR-1，（III）废除胰岛素刺激的Akt和IRS-1磷酸化的胰岛素磷酸化，并在培养的滋养细胞和（IV）置于（IV）孕妇中的孕妇中的置换术中的胎盘抑制作用抑制了孕妇的胎盘，并抑制了孕妇的孕妇的原理。胎儿大小。我们提出了三个特定的目的：（1）确定ADN对胎盘养分传输的影响，并识别受体和介导这些作用的同工型。我们将在ADN和/或胰岛素的生理浓度中孵育培养的人类原发性滋养细胞细胞（有或没有siRNA敲除Adipor1＆2 and Appl 1＆2），并研究葡萄糖和氨基酸的转运蛋白的活性，基因和蛋白质表达。 （2）确定介导ADN对胎盘营养转运蛋白的影响的细胞内信号传导途径。我们将在ADN和/或胰岛素中孵育培养的人类原代滋养细胞细胞，并研究p38MAPK，PPAR-1，IRS-1和AKT的磷酸化和表达。在因果实验中，我们将用siRNA靶向这些信号通路的关键成分，并重新检查ADN对胰岛素信号传导和养分摄取的影响，以及（3）建立母体ADN对胎盘胰岛素信号传导，营养运输和VIVO的影响。在小鼠妊娠的最后一周，我们将通过迷你渗透泵注入ADN。在胚胎第18.5天，我们将研究孕妇代谢，体内胎盘营养转运，胎盘营养转运蛋白表达和胎盘P38MAPK，PPAR-1，IRS-1，IRS-1和AKT信号传导。这项研究具有创新性，因为我们提出了一个新型模型，与ADN相比，ADN与母体外周组织的作用相反，导致胎盘中胰岛素敏感性降低。此外，该建议将导致发现一种新型机制，通过该机制，母体脂肪组织的内分泌功能会影响胎儿的生长。这很重要，因为该模型预测，肥胖和GDM中的低母体ADN提高了胎盘胰岛素敏感性，这有助于增强胎盘营养的运输和胎儿生长。