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: 9768432
• 负责人: Jianhua Shao
• 金额: $ 39.38万
• 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: 2012-08-22 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768432
• 关键词: Achievement; Adenovirus Vector; Adipocytes; Affect; Amino Acids; Biological Availability; Blood Glucose; Body Weight; Cell membrane; Cells; Data; Deposition; Development; Embryo; Endocrine; Endocrine system; Exhibits; Fatty Acids; Fatty acid glycerol esters; Fetal Development; Fetal Growth; Fetal Weight; Fetus; Funding; Glucose; Glucose Intolerance; Hormones; Human; Hyperlipidemia; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Insulin-Like Growth-Factor-Binding Proteins; Knock-out; Knockout Mice; Lead; Link; Long-Term Effects; Low Birth Weight Infant; Measures; Mediating; Metabolic; Metabolism; Modeling; Monitor; Mus; Nutrient; Obesity; Pattern; Placenta; Play; Pregnancy; Pregnancy Proteins; Prevalence; Process; Proteins; Research; Role; Series; Signal Transduction; Syncytiotrophoblast; System; Techniques; Testing; Thinness; Tissues; adiponectin; epidemiology study; fetal; fetal blood; fetal programming; in vivo; infant adiposity; insight; knockout gene; lipid biosynthesis; mouse model; novel; offspring; overexpression; pregnant; protein expression; receptor; spatiotemporal; success; trophoblast

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.

概括 流行病学研究已将肥胖症的原因追溯到宫内胎儿发育。这 肥胖症患病率增加与高出生体重之间的密切联系已进一步加强 肥胖起源的范式。因此，阐明了连接胎儿生长的机制 孕产妇代谢将对肥胖研究产生重大影响。脂联素是脂肪细胞 - 分泌的激素。我们从上一个融资周期的研究表明，母亲和胎儿既有 脂联素可增强胎儿脂肪的积累，但通过不同的机制。胎儿脂联素可以增强脂肪 通过增加从头脂肪生成来发展，而母体脂联素可以通过 减少瘦组织质量。我们的研究使用了一系列鼠标模型，证明了母体 脂联素，但未胎儿脂联素抑制胎儿生长。令我们惊讶的是，与维珍脂联素基因不同 敲除（adipoq - / - ）小鼠，怀孕的adipoq - / - 小鼠表现出葡萄糖不耐症和高脂血症，表明 孕产妇脂联素在调节母体代谢适应怀孕方面起着重要作用。 此外，我们的研究表明，母体脂联素在滋养细胞中增加了IGFBP-1的表达 和胎儿血液IGFBP-1蛋白水平。众所周知，IGFBP-1是IGF-1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-loxp技术，我们 产生的胎盘特异性脂联素受体1（adipor1）或adipor2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，显着敲出了胎盘adipor1 增加胎儿体重。这些数据一起导致我们假设母体脂联素抑制胎儿 通过调节母体代谢，胎儿营养供应和胎儿IGF-1内分泌系统的生长。三 提出了具体目的来检验这一假设。通过恢复Adipoq - / - 大坝中的母体代谢和 直接测量胎盘营养运输速率，特定目标1将研究胎儿营养的作用 母体脂联素抑制的胎儿生长。在特定的目标2中，我们将暴露IGFBP-1 - / - 和WT 胚胎对母体高丙基因血症的胚胎，然后确定IGFBP-1/IGF-1系统在 母体脂联素调节的胎儿生长。 AIM 3的研究将阐明 依次促营养细胞细胞中的脂联素受体，并研究脂联素信号如何有选择地介导 孕产妇但不是胎儿脂联素的调节作用。该项目的预期成功将为 将母体代谢与胎儿内分泌系统和胎儿生长联系起来的新型机制。因此，这个 项目将对肥胖起源的研究产生重大影响。