Adiponectin and fetal programming

脂联素和胎儿编程

• 批准号: 8431780
• 负责人: Jianhua Shao
• 金额: $ 30.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8431780
• 关键词: Adipocytes; Adipose tissue; Adult; Animals; Attenuated; Birth; Blood; Blood Circulation; Body Weight; Brown Fat; CCAAT-Enhancer-Binding Proteins; DNA; DNA Methylation; Diet; Embryo; Environment; Epidemic; Exhibits; Fatty acid glycerol esters; Fetal Weight; Fetus; Fibroblasts; Gene Deletion; Gene Expression; Genes; Genotype; Goals; High birth weight infant; Homeostasis; Hormones; Human; Incidence; Infant; Insulin; Knockout Mice; Lead; Lipids; Lipolysis; Mediating; Metabolic; Metabolism; Methylation; Modeling; Mus; Neonatal; Newborn Infant; Nonesterified Fatty Acids; Obesity; Pathway interactions; Placenta; Play; Pregnancy; Prevalence; Proteins; Reporting; Research Design; Risk; Role; Series; Serum; Tissue Sample; Tissues; Umbilical Cord Blood; United States; Weight Gain; Work; adipocyte differentiation; adiponectin; design; factor C; fatty acid transport; fetal; fetal blood; fetal programming; human study; knockout gene; lipid biosynthesis; lipid metabolism; lipoprotein lipase; mouse model; novel therapeutic intervention; obesity in children; offspring; overexpression; programs; promoter; transcription factor

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.

描述（由申请人提供）：自 1980 年以来，美国儿童肥胖的患病率增加了两倍，达到 17%。最近的人类和动物研究表明，母亲肥胖会增加后代肥胖的风险，这表明胎儿编程发挥着重要作用在肥胖流行中。该项目的最终目标是阐明母亲肥胖改变子宫内代谢环境并影响后代肥胖的潜在机制。 脂联素是一种脂肪细胞衍生的激素，可以使胰岛素敏感并调节能量稳态。 新生儿血液脂联素水平比母体循环高4-7倍。与成人相比，新生儿血液脂联素浓度与婴儿体重呈正相关。研究表明，脂联素可增强小鼠脂肪细胞分化、抑制脂肪分解并增加脂肪组织质量。与人类研究一致，我们的初步小鼠研究表明，母亲肥胖显着增加了胎儿体重。尽管胎盘质量没有变化，但在肥胖母鼠的胎盘中观察到脂蛋白脂肪酶（LPL）基因表达显着增加。肥胖母鼠的胎儿血液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亲肥胖引起的高出生体重和胎盘 LPL 表达。此外，来自肥胖母鼠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高效率，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。肥胖母鼠的 MEF 中 C/EBP2 启动子的甲基化水平显着较低。 脂联素处理增加了 MEF 中 C/EBP2 基因的表达，同时降低了其 DNA 甲基化。因此，我们假设胎儿​​脂联素升高通过增加胎盘脂肪酸转运和减少 C/EBP2 基因甲基化介导母亲肥胖引起的高出生体重和后代肥胖。具体目标 1 的研究旨在使用一系列小鼠模型确定胎儿脂联素在母体肥胖引起的高出生体重和成人肥胖中的作用，这些模型利用脂联素通过胎盘的转运性，并创建了一个独特的模型宫内脂联素缺乏。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的胎儿脂质积累中的作用。通过使用高脂肪饮食诱导的肥胖母鼠和脂联素敲除小鼠，Specific Aim 3将研究母体肥胖的影响以及胎儿脂联素对C/EBP2启动子甲基化的作用。总体而言，该项目将研究胎儿脂联素在母体肥胖程序性后代肥胖中的作用。这些研究将揭示胎儿编程的新途径，从而产生新的治疗方法来阻止母子肥胖的恶性循环。