The maternal-fetal adiponectin differential and fetal fat deposition

摘要 流行病学研究已经将肥胖的原因追溯到胎儿宫内发育。这个 肥胖患病率的增加与出生体重的高低之间的强烈关联进一步得到加强 肥胖症的发育起源范式。因此，阐明与胎儿生长有关的机制 母体新陈代谢将对肥胖研究产生重大影响。脂联素是一种脂肪细胞- 分泌的荷尔蒙。我们在上一个资助周期的研究表明，母体和胎儿 脂联素促进胎儿脂肪堆积，但机制不同。胎儿脂联素增加脂肪 母体脂联素通过增加新生脂肪生成而增加胎儿肥胖症 减少瘦身组织重量。使用一系列小鼠模型，我们的研究表明，母体 抑制胎儿生长的是脂联素，而不是胎儿脂联素。令我们惊讶的是，与原始脂联素基因不同 基因敲除(ADIPOQ-/-)小鼠、怀孕的ADIPOQ-/-小鼠表现出葡萄糖耐受和高脂血症，表明 认为母体脂联素在调节母体对妊娠的代谢适应中起着重要作用。 此外，我们的研究表明，母体脂联素增加了滋养层细胞中IGFBP-1的表达。 和胎儿血中IGFBP-1蛋白水平。已知IGFBP-1是胰岛素样生长因子-1的主要结合蛋白。 胎儿。IGFBP-1抑制IGF-1的生物利用度，抑制胎儿生长。使用CRE-loxP技术，我们 建立胎盘特异性脂联素受体1(AdipoR1)或AdipoR2基因敲除小鼠。我们的预赛 研究表明，与母体脂联素缺乏症类似，胎盘AdipoR1基因显著缺失 胎儿体重增加。综上所述，这些数据使我们假设母体脂联素抑制胎儿 通过调节母体代谢、胎儿营养供应和胎儿IGF-1内分泌系统发育。三 为了检验这一假说，本文提出了具体的目标。通过恢复ADIPOQ-/-DAME和 直接测量胎盘营养物质转运率，特定目标1将调查胎儿营养物质的作用 母体供应脂联素--抑制胎儿生长。在具体目标2中，我们将暴露IGFBP-1-/-和WT 胚胎诱导母体高脂联素血症，进而确定IGFBP-1/IGF-1系统在 母体脂联素调节胎儿生长。对AIM 3的研究将阐明AIM 3的蛋白表达模式 在合体滋养细胞中的脂联素受体，并研究脂联素信号如何选择性地介导 母体脂联素的调节作用，但不是胎儿脂联素。该项目的预期成功将提供一个 将母体新陈代谢与胎儿内分泌系统和胎儿生长联系起来的新机制。因此，这 该项目将对肥胖发育起源的研究产生重大影响。

SUMMARY Epidemiological studies have traced the causes of obesity into intrauterine fetal development. The strong association between increased obesity prevalence and high or low birth weight has further reinforced the paradigm of developmental origins of obesity. Therefore, elucidating the mechanisms that link fetal growth and maternal metabolism will have a significant impact on obesity research. Adiponectin is an adipocyte- secreted hormone. Our studies from the previous funding cycle demonstrated that both maternal and fetal adiponectin enhance fetal fat accumulation but through different mechanisms. Fetal adiponectin enhances fat development by increasing de novo lipogenesis, while maternal adiponectin increases fetal adiposity by reducing lean tissue mass. Using a series of mouse models, our studies demonstrated that maternal adiponectin, but not fetal adiponectin, inhibits fetal growth. To our surprise, unlike virgin adiponectin gene knockout (Adipoq-/-) mice, pregnant Adipoq-/- mice exhibited glucose intolerance and hyperlipidemia, indicating that maternal adiponectin plays an important role in regulating maternal metabolic adaptation to pregnancy. Furthermore, our studies revealed that maternal adiponectin increases IGFBP-1 expression in trophoblast cells and fetal blood IGFBP-1 protein levels. It is known that IGFBP-1 is the predominant binding protein of IGF-1 in fetuses. IGFBP-1 inhibits IGF-1 bioavailability and suppresses fetal growth. Using the Cre-loxp technique, we created placenta-specific adiponectin receptor 1 (AdipoR1) or AdipoR2 gene knockout mice. Our preliminary studies showed that, similar to maternal adiponectin deficiency, knocking out placental AdipoR1 significantly increased fetal weight. Together, these data lead us to hypothesize that maternal adiponectin inhibits fetal growth through modulating maternal metabolism, fetal nutrient supply and fetal IGF-1 endocrine system. Three specific aims are proposed to test this hypothesis. By restoring maternal metabolism in Adipoq-/- dams and directly measuring placental nutrient transport rates, Specific Aim 1 will investigate the role of fetal nutrient supply in maternal adiponectin-inhibited fetal growth. In Specific Aim 2, we will expose IGFBP-1-/- and WT embryos to maternal hyperadiponectinemia, and then determine the role of the IGFBP-1/IGF-1 system in maternal adiponectin-regulated fetal growth. Studies of Aim 3 will clarify the protein expression pattern of adiponectin receptors in syncytiotrophblast cells and study how adiponectin signaling selectively mediates the regulatory effects of maternal but not fetal adiponectin. The anticipated success of this project will provide a novel mechanism that links maternal metabolism to the fetal endocrine system and fetal growth. Therefore, this project will have a significant impact on the research of developmental origins of obesity.