Adiponectin and fetal programming

脂联素和胎儿编程

基本信息

  • 批准号:
    8235753
  • 负责人:
  • 金额:
    $ 32.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-02-22 至 2017-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The prevalence of childhood obesity in the United States has tripled to 17% since 1980. Recent human and animal studies have demonstrated that maternal obesity increases the risk of offspring obesity, which indicate that fetal programming plays an important role in the obesity epidemic. The ultimate goal of this project is to elucidate the underlying mechanisms through which maternal obesity alters the intrauterine metabolic environment and programs offspring obesity. Adiponectin is an adipocyte-derived hormone that sensitizes insulin and regulates energy homeostasis. Blood adiponectin levels of newborns are 4-7 folds higher than that in maternal circulation. In contrast to adults, neonatal blood adiponectin concentrations positively correlate with infant body weight. Studies have shown that adiponectin enhances adipocyte differentiation, inhibits lipolysis and increases adipose tissue mass in mice. Consistent with human studies, our preliminary mouse studies showed that maternal obesity significantly increased fetal body weight. Although there was no change in placenta mass, remarkably increased lipoprotein lipase (LPL) gene expressions were observed in placentas from obese dams. Blood adiponectin concentrations were also significantly increased in fetuses from obese dams. Importantly, adiponectin gene deletion attenuated maternal obesity-induced high birthweight and placental LPL expression. Furthermore, mouse embryonic fibroblasts (MEFs) from obese dams exhibited remarkable high efficiency in adipocyte differentiation, while protein levels of transcription factor C/EBP2 was significantly elevated. A methylation region was identified in the promoter of C/EBP2 gene. The methylation levels of C/EBP2 promoter were significantly low in MEFs from obese dams. Adiponectin treatment increased C/EBP2 gene expression while reduced its DNA methylation in MEFs. Therefore, we hypothesize that elevated fetal adiponectin mediates maternal obesity-induced high birthweight and offspring obesity by increasing placental fatty acid transport and reducing C/EBP2 gene methylation. Studies of Specific Aim 1 are designed to determine the role of fetal adiponectin in maternal obesity-induced high birthweight and adult obesity using a series of mouse models, which take the advantage of the in-transportablility of adiponectin through placenta and create a unique model with intrauterine adiponectin deficiency. Specific Aim 2 will study the effects of fetal adiponectin on placental fatty acid transport. A placenta-specific LPL knockout mouse model will be employed to verify the role of placental LPL in maternal obesity-induced high birthweight and adiponectin-enhanced fetal lipid accumulation. By using high fat diet-induced obese dams and adiponectin knockout mice, Specific Aim 3 will study the effects of maternal obesity and the role of fetal adiponectin on C/EBP2 promoter methylation. Overall, this project will investigate the role of fetal adiponectin in maternal obesity-programmed offspring adiposity. These studies will reveal new pathways of fetal programming that will lead to new therapeutic approaches to stop the vicious cycle of maternal-offspring obesity. PUBLIC HEALTH RELEVANCE: This project will investigate the role of fetal adiponectin in maternal obesity-programmed offspring adiposity. The designed studies will reveal new pathways of fetal programming that may lead to a new therapeutic approach to stop the maternal-offspring obesity vicious cycle.
描述(由申请人提供):自1980年以来,美国儿童肥胖症的患病率已增加了两倍。最近的人类和动物研究表明,孕产妇肥胖会增加后代肥胖的风险,这表明胎儿编程在肥胖症流行中起着重要作用。该项目的最终目标是阐明产妇肥胖来改变宫内代谢环境和后代肥胖的潜在机制。 脂联素是一种脂肪细胞衍生的激素,可使胰岛素敏感并调节能量稳态。 新生儿的血脂联素水平比母体循环高4-7倍。与成年人相反,新生儿血脂联素浓度与婴儿体重正相关。研究表明,脂联素可以增强脂肪细胞分化,抑制脂肪分解并增加小鼠的脂肪组织质量。与人类研究一致,我们的初步小鼠研究表明,孕产妇肥胖显着增加了胎儿体重。尽管胎盘质量没有变化,但在肥胖大坝的胎盘中观察到脂蛋白脂肪酶(LPL)基因表达的升高。肥胖大坝的胎儿的血脂联素浓度也显着增加。重要的是,脂联素基因缺失减弱了母体肥胖引起的高出生体重和胎盘LPL表达。此外,来自肥胖大坝的小鼠胚胎成纤维细胞(MEF)在脂肪细胞分化方面表现出显着的效率,而转录因子C/EBP2的蛋白质水平显着升高。在C/EBP2基因的启动子中鉴定出甲基化区域。来自肥胖大坝的MEF的C/EBP2启动子的甲基化水平明显低。 脂联素治疗增加了C/EBP2基因的表达,而其DNA甲基化降低了MEF中的DNA甲基化。因此,我们假设升高的胎儿脂联素通过增加胎盘脂肪酸的转运并减少C/EBP2基因甲基化,从而介导了母体肥胖引起的高出生体重和后代肥胖。对特定目标1的研究旨在确定胎儿脂联素在产妇肥胖诱导的高出生体重和成人肥胖中的作用,使用一系列小鼠模型可以利用脂联素通过胎盘的不可传输性,并使用肠内脂联蛋白缺乏症创建独特的模型。具体目标2将研究胎儿脂联素对胎盘脂肪酸转运的影响。将采用胎盘特异性LPL敲除小鼠模型来验证胎盘LPL在母体肥胖引起的高出生体重和脂联素增强胎儿脂质积累中的作用。通过使用高脂肪饮食诱导的肥胖大坝和脂联素基因敲除小鼠,特定的目标3将研究孕产妇肥胖的作用以及胎儿脂联素对C/EBP2启动子甲基化的作用。总体而言,该项目将调查胎儿脂联素在母体肥胖症中的作用。这些研究将揭示胎儿编程的新途径,这将导致新的治疗方法,以阻止孕产妇的恶性循环。 公共卫生相关性:该项目将调查胎儿脂联素在孕产妇肥胖的后代肥胖性中的作用。设计的研究将揭示胎儿编程的新途径,这可能会导致一种新的治疗方法,以阻止孕产妇的肥胖循环。

项目成果

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Jianhua Shao其他文献

Jianhua Shao的其他文献

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{{ truncateString('Jianhua Shao', 18)}}的其他基金

Pancreatic alpha-cells and Maternal metabolic Adaptation
胰腺α细胞和母体代谢适应
  • 批准号:
    10681909
  • 财政年份:
    2023
  • 资助金额:
    $ 32.12万
  • 项目类别:
Alpha cell-derived Extracellular Vesicles and Maternal Insulin Production
α细胞来源的细胞外囊泡和母体胰岛素的产生
  • 批准号:
    10681939
  • 财政年份:
    2023
  • 资助金额:
    $ 32.12万
  • 项目类别:
Brown adipose tissue development and fetal growth
棕色脂肪组织发育和胎儿生长
  • 批准号:
    10539636
  • 财政年份:
    2022
  • 资助金额:
    $ 32.12万
  • 项目类别:
Brown adipose tissue development and fetal growth
棕色脂肪组织发育和胎儿生长
  • 批准号:
    10687215
  • 财政年份:
    2022
  • 资助金额:
    $ 32.12万
  • 项目类别:
Hypoadiponectinemia and Gestational Diabetes
低脂联素血症和妊娠期糖尿病
  • 批准号:
    10063518
  • 财政年份:
    2017
  • 资助金额:
    $ 32.12万
  • 项目类别:
Hypoadiponectinemia and Gestational Diabetes
低脂联素血症和妊娠期糖尿病
  • 批准号:
    10753827
  • 财政年份:
    2017
  • 资助金额:
    $ 32.12万
  • 项目类别:
The maternal-fetal adiponectin differential and fetal fat deposition
母胎脂联素差异和胎儿脂肪沉积
  • 批准号:
    8900277
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Adiponectin and fetal programming
脂联素和胎儿编程
  • 批准号:
    8431780
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
Adiponectin and fetal programming
脂联素和胎儿编程
  • 批准号:
    8610337
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:
The maternal-fetal adiponectin differential and fetal fat deposition
母胎脂联素差异和胎儿脂肪沉积
  • 批准号:
    9768432
  • 财政年份:
    2012
  • 资助金额:
    $ 32.12万
  • 项目类别:

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空气污染介导的肥胖加剧中的肾素-血管紧张素系统。
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