The maternal-fetal adiponectin differential and fetal fat deposition

母胎脂联素差异和胎儿脂肪沉积

基本信息

批准号：
8708063
负责人：
Jianhua Shao
金额：
$ 32.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708063
关键词：
Adipocytes Adipose tissue Adult Animals Attenuated Biological Markers Blood Blood Circulation Body Weight Body fat Breeding Clinical Cyclic AMP-Dependent Protein Kinases Deposition Diet Energy Metabolism Environment Exhibits Fatty Acids Fatty acid glycerol esters Fetal Development Fetal Liver Fetal Weight Fetus Gene Expression Genes Genotype Goals Hepatic High birth weight infant Homeostasis Hormones Hydrolysis Infant Knockout Mice Label Lead Length Life Lipids Lipolysis Liver Mediating Metabolic Metabolism Modeling Mus Neonatal Obesity Partner in relationship Placenta Play Predisposition Pregnancy Process Reporting Research Design Role Series Tissues Triglycerides Weight Work adipocyte differentiation adiponectin design fetal fetal blood fetal programming improved in utero in vivo infancy insulin signaling knockout gene lipid biosynthesis lipid metabolism lipoprotein lipase mouse model novel therapeutic intervention obesity in children offspring overexpression postnatal programs uptake very low density lipoprotein triglyceride

项目摘要

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.

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子宫内代谢环境并影响后代肥胖。脂联素是一种脂肪细胞分泌的激素，其主要功能是维持能量稳态。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升高。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（约 4-7 倍）。我们将这种差异称为母胎脂联素差异（MFAD）。与成人相比，新生儿血液脂联素水平与肥胖的人体测量参数呈正相关。脂联素可增强脂肪细胞中的脂质积累并增加小鼠的脂肪组织质量。我们的初步研究表明，母亲肥胖会增加胎儿小鼠脂肪组织质量，胎儿血液中脂联素显着升高。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量，这表明脂联素在胎儿脂肪沉积中发挥重要作用。使用另一种控制母体脂联素水平的胎儿小鼠模型，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-/+ 胎儿的以下水平显着较高：1) 身体脂肪； 2) 与 Adipoq-/- 胎儿相比，肝脏甘油三酯含量和从头生脂基因的表达以及 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质代谢，并通过增加胎儿肝脏从头脂肪生成和脂质积累来增强胎儿脂肪沉积。母亲肥胖会进一步增加 MFAD，从而诱导更多的胎儿脂肪沉积。将使用具有不同 MFAD 水平的小鼠模型进行一系列体内研究。具体目标 1 将比较在子宫内暴露于 MFAD 或未暴露于 MFAD 的后代从婴儿期到成年期的肥胖情况。还将研究 MFAD 增加在母亲肥胖增强胎儿脂肪沉积中的作用。具体目标2旨在确定母亲肥胖是否会诱导胎儿肝脏从头脂肪生成，并检查脂联素对胎儿肝脏从头脂肪生成的调节作用。具体目标 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的甘油三酯水解和脂肪酸摄取。角色将使用诱导型脂肪细胞特异性 LPL 敲除小鼠来研究 LPL 在这些过程中的作用。该项目的研究结果应将脂联素确定为一种关键激素，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，该项目将显着提高我们对母亲肥胖引起的后代肥胖的理解。