The maternal-fetal adiponectin differential and fetal fat deposition

描述(由申请人提供)：我们的长期目标是阐明母体肥胖如何改变宫内代谢环境和子代肥胖计划。脂联素是一种脂肪细胞分泌的激素，在维持能量平衡方面具有重要作用。在妊娠晚期，母体脂联素水平稳步下降，而胎儿脂联素水平迅速上升。脂联素不能通过胎盘屏障。分娩时，胎儿和母体血液中的脂联素水平存在巨大差异(~4-7倍)。我们称这种差异为母胎脂联素差异(MFAD)。与成人相比，新生儿血脂联素水平与肥胖的人体测量参数呈正相关。脂联素增加脂肪细胞中的脂肪积聚，增加小鼠的脂肪组织质量。我们的初步研究表明，母亲肥胖增加了胎鼠脂肪组织质量，胎儿血液中的脂联素显着增加。然而，在脂联素基因敲除(ADIPOQ-/-)小鼠中，母亲肥胖并没有增加胎儿体重和脂肪组织质量，这表明脂联素在胎儿脂肪沉积中起着重要作用。利用另一种控制母体脂联素水平的胎鼠模型，进一步研究了脂联素对胎儿脂代谢的调节作用。我们发现，与ADIPOQ-/-胎儿相比，ADIPOQ-/胎儿在以下方面的水平显著高于ADIPOQ-/-胎儿：1)体脂；2)肝脏甘油三酯含量和新生成脂基因的表达；3)脂肪组织中的脂蛋白脂肪酶(LPL)。因此，我们假设，在妊娠晚期，MFAD协调母体和胎儿的脂肪代谢，并通过增加胎儿肝脏新生脂肪生成和脂肪积累来促进胎儿脂肪沉积。母亲肥胖进一步增加了MFAD，从而导致更多的胎儿脂肪沉积。将使用不同水平的MFAD的小鼠模型进行一系列体内研究。具体目标1将比较在子宫中暴露或未暴露于MFAD的后代从婴儿期到成年期的肥胖情况。MFAD增加在母亲肥胖促进胎儿脂肪沉积中的作用也将被研究。特异目的2旨在确定母亲肥胖是否诱导胎肝新生脂肪生成，并检测脂联素对胎肝新生脂肪生成的调节作用。两项研究将在特定的目标3中进行，以调查胎儿脂联素升高是否会刺激胎儿脂肪组织中甘油三酯的水解和脂肪酸的摄取。角色 将使用可诱导的脂肪细胞特异性LPL基因敲除小鼠来研究LPL在这些过程中的作用。该项目的发现应该确定脂联素是一种关键激素，通过母体和胎儿循环中脂联素水平的相反变化来调节有利于胎儿脂肪沉积的宫内代谢环境。重要的是，这个项目将显著提高我们对母体肥胖引起的子代肥胖的理解。

DESCRIPTION (provided by applicant): Our longterm goal is to elucidate how maternal obesity alters the intrauterine metabolic environment and programs offspring obesity. Adiponectin is an adipocyte-secreted hormone with a predominant function in maintaining energy homeostasis. During late pregnancy, maternal adiponectin levels decrease steadily, while fetal adiponectin levels increase rapidly. Adiponectin cannot pass through the placenta barrier. At delivery, a huge difference (~4-7-fold) in blood adiponectin levels between fetal and maternal blood exists. We call this difference the maternal-fetal adiponectin differential (MFAD). In contrast to adults, neonatal blood adiponectin levels are positively correlated with anthropometric parameters of adiposity. Adiponectin enhances lipid accumulation in adipocytes and increase fat tissue mass in mice. Our preliminary study showed that maternal obesity increases fetal mouse fat tissue mass with a significant elevation of adiponectin in fetal blood. However, in adiponectin gene knockout (Adipoq-/-) mice, maternal obesity failed to increase fetal body weight and fat tissue mass, which suggests that adiponectin plays an important role in fetal fat deposition. Using another fetal mouse model with controlled maternal adiponectin levels, we further studied the regulatory effects of adiponectin on fetal lipid metabolism. We found that Adipoq-/+ fetuses have significantly higher levels of: 1) body fat; 2) liver triglycerid content and expression of de novo lipogenic genes and 3) lipoprotein lipase (LPL) in fat tissue, compared with Adipoq-/- fetuses. Therefore, we hypothesize that during late gestation; the MFAD coordinates both maternal and fetal lipid metabolism, and enhances fetal fat deposition by increasing fetal hepatic de novo lipogenesis and lipid accumulation. Maternal obesity further increases the MFAD, which induces more fetal fat deposition. A series of in vivo studies will be carried out using mouse models with various levels of the MFAD. Specific aim 1 will compare the adiposity of offspring from infancy to adulthood who are either exposed in utero or not to the MFAD. The role of increased MFAD in maternal obesity-enhanced fetal fat deposition will also be studied. Specific Aim 2 is designed to determine whether maternal obesity induces fetal liver de novo lipogenesis, and to examine the regulatory effects of adiponectin on fetal liver de novo lipogenesis. Two studies will be carried out in Specific Aim 3 to investigate if elevated fetal adiponectin stimulates triglyceride hydrolysis and fatty acid uptake in fetal fat tissues. The role of LPL in these processes will be studied using inducible adipocyte-specific LPL knockout mice. The findings of this project should identify adiponectin as a key hormone that regulates the intrauterine metabolic environment favoring fetal fat deposition via opposite changes of adiponectin levels in maternal and fetal circulation. Importantly, this project will significantly improve our understanding of maternal obesity-induced offspring adiposity.