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亲肥胖如何改变宫内代谢环境和影响后代肥胖。脂联素是一种脂肪细胞分泌的激素，在维持能量稳态中起主要作用。在妊娠后期，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。在分娩时，胎儿和母亲血液中的脂联素水平存在巨大差异（约4-7倍）。我们称这种差异为母胎脂联素差异（MFAD）。与成人相反，新生儿血液脂联素水平与肥胖的人体测量参数呈正相关。脂联素促进脂肪细胞脂质积累，增加小鼠脂肪组织质量。我们的初步研究表明，母亲肥胖增加胎儿小鼠脂肪组织质量，胎儿血液中脂联素显著升高。然而，在脂联素基因敲除（Adipoq-/-）小鼠中，母体肥胖未能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重要作用。通过另一种控制母体脂联素水平的胎鼠模型，我们进一步研究了脂联素对胎儿脂质代谢的调节作用。我们发现Adipoq-/+的胎儿有明显更高的水平：1)体脂；2)肝脏甘油三酯含量和新生脂肪基因表达；3)脂肪组织脂蛋白脂肪酶（LPL）与Adipoq-/-胎儿比较。因此，我们假设在妊娠后期；MFAD协调母体和胎儿的脂质代谢，并通过增加胎儿肝脏新生脂肪生成和脂质积累来促进胎儿脂肪沉积。母亲肥胖进一步增加了MFAD，导致更多的胎儿脂肪沉积。一系列的体内研究将使用具有不同水平MFAD的小鼠模型进行。具体目标1将比较在子宫内或未暴露于MFAD的后代从婴儿期到成年期的肥胖情况。MFAD的增加在母体肥胖和胎儿脂肪沉积中的作用也将被研究。特异性目的2旨在确定母体肥胖是否诱导胎儿肝脏新生脂肪形成，并研究脂联素对胎儿肝脏新生脂肪形成的调节作用。特异性目的3将进行两项研究，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水解和脂肪酸摄取。这个角色

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.