Adiponectin and fetal programming

描述(申请人提供)：自1980年以来，美国儿童肥胖症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。这个项目的最终目标是阐明母体肥胖改变宫内代谢环境和子代肥胖的潜在机制。脂联素是一种脂肪细胞衍生的激素，能敏化胰岛素并调节能量平衡。新生儿的血脂联素水平是母体循环的4-7倍。与成人相比，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，母亲肥胖显著增加了胎儿体重。虽然胎盘质量没有变化，但肥胖大鼠胎盘中脂蛋白脂酶(LPL)基因的表达显著增加。来自肥胖水坝的胎儿的血脂联素浓度也显著增加。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，来自肥胖大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域。肥胖大鼠骨髓间充质干细胞中C/EBP2启动子甲基化水平显著降低。脂联素治疗可增加MEF中C/EBP2基因的表达，降低其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基因甲基化来介导母亲肥胖引起的新生儿高体重和后代肥胖。特定目的1的研究旨在通过一系列小鼠模型来确定胎儿脂联素在母体肥胖引起的新生儿高体重和成人肥胖中的作用，该模型利用脂联素可通过胎盘转运的优势，建立了一种独特的宫内脂联素缺乏模型。具体目标2将研究胎儿脂联素对胎盘脂肪酸运输的影响。胎盘特异的LPL基因敲除小鼠模型将被用来验证胎盘LPL在母体肥胖导致的高出生体重和脂联素增强的胎儿脂肪积累中的作用。通过使用高脂饮食诱导的肥胖大鼠和脂联素基因敲除小鼠，特定目标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。总体而言，该项目将调查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，以阻止母子肥胖的恶性循环。

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.