The maternal-fetal adiponectin differential and fetal fat deposition

总结 流行病学研究已经将肥胖的原因追溯到子宫内胎儿的发育。的 肥胖患病率的增加与出生体重过高或过低之间的密切联系进一步加强了 肥胖的发展起源的范式。因此，阐明胎儿生长的机制 和母体代谢将对肥胖研究产生重大影响。脂联素是脂肪细胞 分泌的荷尔蒙我们从上一个资助周期的研究表明，产妇和胎儿 脂联素通过不同的机制促进胎儿脂肪的积累。胎儿脂联素增加脂肪 通过增加新生脂肪生成，而母体脂联素通过增加胎儿肥胖， 减少瘦组织质量。使用一系列小鼠模型，我们的研究表明，母体 脂联素而不是胎儿脂联素抑制胎儿生长。令我们惊讶的是，与处女脂联素基因不同， 敲除（Adipoq-/-）小鼠，妊娠Adipoq-/-小鼠表现出葡萄糖耐受不良和高脂血症，表明 母体脂联素在调节母体妊娠代谢适应中起重要作用。 此外，我们的研究表明，母体脂联素增加滋养层细胞IGFBP-1的表达， 和胎儿血液IGFBP-1蛋白水平。已知IGFBP-I是IGF-I的主要结合蛋白， 胎儿IGFBP-1抑制IGF-1生物利用度并抑制胎儿生长。使用Cre-locp技术，我们 建立胎盘特异性脂联素受体1（AdipoR 1）或AdipoR 2基因敲除小鼠。我们的初步 研究表明，类似于母体脂联素缺乏症， 胎儿体重增加。总之，这些数据使我们假设母体脂联素抑制胎儿生长， 通过调节母体代谢、胎儿营养供应和胎儿IGF-1内分泌系统来促进生长。三 提出了具体目标来检验这一假设。通过恢复Adipoq-/-母鼠的母体代谢， 直接测量胎盘营养转运率，具体目标1将研究胎儿营养的作用， 母体脂联素供应抑制胎儿生长。在特定目标2中，我们将暴露IGFBP-1-/-和WT 胚胎对母体高脂联素血症的影响，然后确定IGFBP-1/IGF-1系统在 母体脂联素调节胎儿生长。目的3的研究将阐明蛋白表达模式， 脂联素受体在合体滋养层细胞和研究脂联素信号如何选择性介导 母体脂联素的调节作用，而不是胎儿脂联素。该项目的预期成功将提供一个 将母体代谢与胎儿内分泌系统和胎儿生长联系起来的新机制。因此本 该项目将对肥胖的发育起源研究产生重大影响。

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.