Adiponectin and fetal programming

脂联素和胎儿编程

• 批准号: 8610337
• 负责人: Jianhua Shao
• 金额: $ 31.26万
• 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/8610337
• 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; Peroxisome Proliferator-Activated Receptors; 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，这表明胎儿编程在肥胖流行中起着重要作用。本项目的最终目的是阐明母体肥胖改变宫内代谢环境和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，可使胰岛素增敏并调节能量稳态。新生儿血脂联素水平比母体高4-7倍。与成人相反，新生儿血脂联素浓度与婴儿体重呈正相关。研究表明，脂联素能促进小鼠脂肪细胞分化，抑制脂肪分解，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，母亲肥胖显著增加胎儿体重。虽然胎盘质量没有变化，但脂蛋白脂肪酶（LPL）基因在肥胖母鼠胎盘中的表达显著增加。肥胖胎儿的血脂联素浓度也显著升高。重要的是，脂联素基因缺失减轻了母亲肥胖引起的高出生体重和胎盘LPL的表达。此外，肥胖小鼠胚胎成纤维细胞（MEFs）在脂肪细胞分化方面表现出显著的高效率，同时转录因子C/EBP2的蛋白水平显著升高。在C/EBP2基因启动子中发现了一个甲基化区。肥胖坝mef中C/EBP2启动子甲基化水平明显较低。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基因甲基化介导了母亲肥胖引起的高出生体重和后代肥胖。Specific Aim 1的研究旨在通过一系列小鼠模型确定胎儿脂联素在母体肥胖诱导的高出生体重和成人肥胖中的作用，利用脂联素通过胎盘的不可转运性，创建一个独特的宫内脂联素缺乏模型。特异性目的2将研究胎儿脂联素对胎盘脂肪酸运输的影响。我们将采用胎盘特异性LPL敲除小鼠模型来验证胎盘LPL在母体肥胖诱导的高出生体重和脂联素增强的胎儿脂质积累中的作用。通过高脂饮食诱导的肥胖小鼠和脂联素敲除小鼠，Specific Aim 3将研究母体肥胖的影响和胎儿脂联素对C/EBP2启动子甲基化的作用。总之，本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，这将导致新的治疗方法来阻止母体-后代肥胖的恶性循环。