Placental adiponectin signaling and fetal programming in maternal obesity

孕产妇肥胖中的胎盘脂联素信号传导和胎儿编程

• 批准号: 10164820
• 负责人: Thomas Jansson
• 金额: $ 42.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164820
• 关键词: Address; Adult; Adverse effects; Age-Months; American; Amino Acids; Animal Model; Anti-Obesity Agents; Attenuated; Birth; Birth Weight; Blood Pressure; Body Composition; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cells; Ceramides; Child; Childhood; Chronic Disease; Closure by clamp; Data; Development; Diabetes Mellitus; Dietary Intervention; Disease; Echocardiography; Environment; Exposure to; FRAP1 gene; Fasting; Fatty Liver; Fatty acid glycerol esters; Female; Fetal Growth; Fetal Macrosomia; Fetus; Functional disorder; Gene Activation; Gestational Age; Glucose Intolerance; Heart Hypertrophy; Hormones; Human; Hypertriglyceridemia; Infant; Insulin; Insulin Resistance; Intervention; Late pregnancy; Lead; Left; Leptin; Life; Life Style; Link; Liver; Magnetic Resonance Imaging; Mediating; Meta-Analysis; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mothers; Mus; Nutrient; Obesity; Overweight; PPAR alpha; Peripheral; Peroxisome Proliferator-Activated Receptors; Placenta; Pregnancy; Pregnant Women; Public Health; Pump; Reporting; Risk; Role; Serum; Signal Transduction; Skeletal Muscle; Structure; Supplementation; Telemetry; Testing; Thinness; Tissues; Up-Regulation; Ventricular; Woman; Work; adiponectin; adverse outcome; effective therapy; fetal; fetal hyperglycemia; fetal programming; glucose tolerance; heart function; in utero; in vivo; insulin sensitivity; insulin sensitizing drugs; insulin signaling; knock-down; lifestyle intervention; liver metabolism; male; maternal obesity; maternal serum; mouse model; next generation; novel; obese mothers; obesity in children; obesity risk; obstetric outcomes; offspring; pregnant; prevent; public health relevance; receptor; response; restoration; transmission process; trophoblast

Over 60% of American women now enter pregnancy either overweight or obese, which increases the risk for the infant to develop obesity, diabetes and cardiovascular disease in childhood and later in life. However, the mechanisms linking the in utero environment in maternal obesity to programming of the fetus for later disease remain poorly understood, which constitutes a major roadblock for the development of specific intervention strategies. Circulating levels of adiponectin are decreased in obese pregnant women and in our mouse model of maternal obesity. We have previously reported that adiponectin, in contrast to its well-known insulin- sensitizing effects in skeletal muscle and liver, inhibits placental insulin and mTOR signaling and amino acid transport. This effect is mediated by activation of trophoblast PPARsignaling, which increases ceramide synthesis resulting in inhibition of IRS-1. Remarkably, in our novel model of maternal obesity, which shows extensive similarities with the human condition (elevated levels of maternal leptin, glucose intolerance, activation of placental insulin and mTOR signaling, increased placental nutrient transport and fetal overgrowth), restoration of normal circulating levels of adiponectin completely prevented placental dysfunction, fetal hyperglycemia and overgrowth. Our findings demonstrate that low circulating adiponectin in maternal obesity is mechanistically linked to increased placental nutrient transport and fetal growth. However, whether normalization of maternal adiponectin levels in pregnancy attenuates the long-term adverse metabolic and cardiovascular consequences of intrauterine exposure to maternal obesity in the offspring is unknown. Our central hypothesis is that adiponectin supplementation in late pregnancy prevents the development of metabolic and cardiovascular disease in the offspring in response to maternal obesity and that this effect is mediated by adiponectin receptor 2 (AdipoR2) in the placenta. This hypothesis is supported by compelling preliminary data including the demonstration that 3-month old male offspring of obese dams (1) develop obesity, glucose intolerance, hypertriglyceridemia and fatty liver; (2) have up-regulation of fetal cardiac genes, activation of cardiac insulin and mTOR signaling and left ventricular diastolic dysfunction and (3) these developmentally programmed changes are prevented by maternal adiponectin supplementation in pregnancy. Using mini-osmotic pumps, we will supplement adiponectin the last four days of pregnancy to lean and obese dams, with or without trophoblast-specific knock down of AdipoR2, and study male and female offspring at 3 and 6 months of age to address our hypothesis in three specific aims: Determine the effect of adiponectin supplementation in obese dams on offspring metabolism (Aim 1) and cardiovascular function (Aim 2) and to determine the mechanistic role of placental adiponectin receptors in fetal programming in maternal obesity (Aim 3). This work will have a significant and sustained impact on the field because it will lead to a better understanding of the mechanistic role of the placenta in mediating in utero programming and may lead to novel specific intervention strategies to alleviate the adverse effects of maternal obesity on the offspring.

超过60%的美国女性现在进入怀孕阶段，要么超重，要么肥胖，这增加了患上 婴儿在童年和以后的生活中会患上肥胖症、糖尿病和心血管疾病。然而， 母体肥胖的宫内环境与胎儿日后疾病规划的联系机制 仍然知之甚少，这构成了制定具体干预措施的主要障碍 战略。肥胖孕妇和我们的小鼠模型循环中的脂联素水平降低 母体肥胖症。我们之前已经报道过脂联素，与其众所周知的胰岛素相反- 骨骼肌和肝脏的增敏作用，抑制胎盘胰岛素和mTOR信号及氨基酸 运输。这种作用是通过激活滋养层细胞PPAR信号，从而增加神经酰胺来实现的 合成导致对IRS-1的抑制。值得注意的是，在我们新的母体肥胖模型中，这表明 与人类的情况有广泛的相似之处(孕妇瘦素水平升高，葡萄糖耐受， 胎盘胰岛素和mTOR信号的激活，胎盘营养物质转运的增加和胎儿过度生长)， 恢复正常循环脂联素水平完全防止胎盘功能障碍，胎儿 高血糖和过度生长。我们的研究结果表明，低循环脂联素在母亲肥胖中是 从机制上讲，这与胎盘营养物质转运增加和胎儿生长有关。然而，无论是 妊娠期母体脂联素水平正常化可减轻长期不良代谢和 宫内暴露于母体肥胖对子代的心血管后果尚不清楚。我们的 中心假说是妊娠晚期补充脂联素可防止糖尿病的发生。 母体肥胖对子代的代谢和心血管疾病的影响 由胎盘中的脂联素受体2(AdipoR2)介导。这一假设得到了令人信服的支持 初步数据包括肥胖母鸡3个月大的雄性后代发育情况(1) 肥胖、糖耐量低减、高甘油三酯血症和脂肪肝；(2)胎儿心脏基因上调， 心脏胰岛素和mTOR信号通路的激活与左室舒张功能不全 孕期补充脂联素可防止发育程序性改变。 使用微型渗透泵，我们将在怀孕的最后四天补充脂联素，以帮助瘦身和肥胖的人 有或没有滋养细胞特异性AdipoR2基因敲除的母鼠，并研究3岁时的雄性和雌性后代 和6个月龄来解决我们的假设的三个具体目标：确定脂联素的效果 肥胖母鼠补充营养对子代代谢(目标1)和心血管功能(目标2)的影响 确定胎盘脂联素受体在母体肥胖的胎盘计划中的机制作用 (目标3)。这项工作将对实地产生重大和持久的影响，因为它将导致更好的 了解胎盘在调节子宫编程中的机械作用并可能导致新的 减轻母体肥胖对子代不利影响的具体干预策略。