The maternal-fetal adiponectin differential and fetal fat deposition

母胎脂联素差异和胎儿脂肪沉积

• 批准号: 8900277
• 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
• 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/8900277
• 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

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孕产妇肥胖如何改变宫内代谢环境和计划后代肥胖。脂联素是一种脂肪细胞分泌的激素，在维持能量稳态方面具有主要功能。在怀孕后期，母体脂联素水平稳定下降，而胎儿脂联素水平迅速升高。脂联素无法通过胎盘屏障。分娩时，存在血液和母体血液之间血液脂联素水平的巨大差异（约4-7倍）。我们称这种差异为母亲脂联蛋白差异（MFAD）。与成年人相反，新生儿血脂联素水平与肥胖的人体测量学参数呈正相关。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肿块。我们的初步研究表明，孕产妇肥胖会增加胎儿小鼠脂肪组织质量，胎儿血液中脂联素的显着升高。然而，在脂联素基因敲除（adipoq - / - ）小鼠中，产妇肥胖症未能增加胎儿体重和脂肪组织肿块，这表明脂联素在胎儿脂肪沉积中起重要作用。使用另一个具有受控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 - /+胎儿的水平明显更高：1）体内脂肪； 2）与adipoq - / - 胎儿相比，脂肪蛋白脂肪酶（LPL）的肝甘油三酸酯含量和脂肪蛋白脂肪酶（LPL）的表达与脂蛋白脂肪酶（LPL）。因此，我们假设在妊娠晚期。 MFAD协调母体和胎儿脂质代谢，并通过增加胎儿肝脂肪生成和脂质积累来增强胎儿脂肪沉积。孕产妇肥胖进一步增加了MFAD，这会诱导更多的胎儿脂肪沉积。使用具有不同级别MFAD的小鼠模型将进行一系列体内研究。特定的目标1将比较从婴儿期到成年后代的肥胖，他们要么在子宫内暴露或不暴露于MFAD。还将研究MFAD在孕产妇增强胎儿脂肪沉积中的作用。特定目标2旨在确定母体肥胖是否诱导胎儿肝脏脂肪生成，并检查脂联素对胎儿肝脏脂肪生成的调节作用。在特定目标3中将进行两项研究，以研究胎儿脂肪组织中甘油三酸酯的水解和脂肪酸摄取是否刺激胎儿脂肪组织的摄入。角色 这些过程中的LPL将使用诱导脂肪细胞特异性LPL基因敲除小鼠进行研究。该项目的发现应鉴定脂联素是一种关键激素，该激素调节了宫内的代谢环境，有利于胎儿脂肪沉积在母体和胎儿循环中的相反变化。重要的是，该项目将显着提高我们对孕产妇肥胖引起的后代肥胖的理解。