IUGR蒙古绵羊胎儿肾周脂肪线粒体生物合成程序化改变及其阻滞褐色脂肪细胞发育分化分子机理研究

Intrauterine growth restriction (IUGR) caused by maternal undernutrition is a relatively common condition, which induce programming modifications of mitochondrial biogenesis in fetal perirenal adipose severely, and result in retardation of fetal brown adipocytes development and hypothermia of neonatal lamb with very high morbidity and mortality. However, the mechanisms remain unclear. Therefore, this study intends to analyze the effects of IUGR on growth and development of fetal perirenal adipose tissue and the programming modifications of mitochondrial biogenesis in ovine fetal perirenal adipose, measure the concentrations of extracellular growth factors, the gene and protein expressions of their receptors in IUGR ovine fetal perirenal adipose, determine the main cell signaling pathways manipulating the programming modifications of ovine fetal mitochondrial biogenesis in perirenal adipose and their relationships, investigate the retarding mechanisms of the main cell signaling pathways to the development and differentiation of brown adipocyte, in order to reveal the trinity molecular signal network of extracellular growth factors and their receptors - Regulating signaling pathways in programming modifications of fetal mitochondrial biogenesis - Brown adipocyte development based on the four layer model including organ, cell, organelle and molecular factors, and clarify molecular mechanisms underlying the programming modifications of mitochondrial biogenesis and retardation of brown adipocyte development in IUGR ovine fetal perirenal adipose, supply references for improving the scientific feeding and management, the anti-disaster and animal protection capacity during the winter-spring grazing season of north China as well as the researches correlated in medical science.

母体营养缺乏导致的胎儿宫内生长受限（IUGR）是一种普遍现象，它严重诱发胎儿肾周脂肪线粒体生物合成程序性改变而导致褐色脂肪发育受阻、初生羔羊低体温症高死亡率，但机理仍不很清楚。因此，本项目拟通过分析IUGR影响绵羊胎儿肾周脂肪生长发育及其线粒体生物合成程序性改变的一般规律，测定IUGR胎儿肾周脂肪细胞外生长因子及其受体表达变化，明确IUGR调控脂肪细胞内线粒体生物合成程序性改变主效信号通路及相互关系，研究主效信号通路调控IUGR胎儿肾周褐色脂肪发育分化机理，从器官、细胞、细胞器和分子的四个层次系统揭示IUGR绵羊胎儿肾周脂肪细胞外生长因子及其受体-线粒体生物合成程序性改变信号通路-褐色脂肪细胞发育分化受阻三位一体的分子调控信号网络，阐明IUGR绵羊胎儿肾周脂肪线粒体生物合成程序性改变及其阻滞褐色脂肪发育分化机理，为完善北方草原地区冬春科学的饲养管理制度、抗灾保畜及医学相关研究提供参考依据。

母体营养缺乏导致的胎儿宫内生长受限（IUGR）是一种普遍现象，它严重诱发胎儿肾周脂肪线粒体生物合成程序性改变而导致褐色脂肪发育受阻、初生羔羊低体温症和高死亡率，但机理仍不很清楚。因此，本项目开展了IUGR蒙古绵羊胎儿肾周脂肪线粒体生物合成程序化改变及其阻滞褐色脂肪细胞发育分化分子机理研究。结果表明：随着母体营养水平的降低，RG1组胎儿肾周脂肪重（P<0.01）和生长速率（P<0.05）显著低于CG组，线粒体DNA含量、线粒体DNA拷贝数、肾周脂肪耗氧量显著低于CG组（P<0.05）。进一步对线粒体呼吸链复合体研究发现，RG1组胎儿肾周脂肪线粒体呼吸链复合体Ⅰ（P<0.01）、复合体Ⅱ（P<0.05）、复合体Ⅲ（P<0.01）、柠檬酸合酶（P<0.05）、UCP1基因表达量（P<0.05）、UCP1蛋白含量（P<0.01）显著低于CG组，而RG2组复合体Ⅰ（P<0.01）、复合体Ⅱ（P<0.05）、复合体Ⅲ（P<0.05）、UCP1蛋白含量（P<0.05）显著低于CG组。细胞周期调控相关分析发现RG1和RG2组周期调控基因CCNA、CCNB、CCND、CDK1、E2F1、E2F4、E2F5显著低于对照组（P<0.05）。RG1组IGF1R受体蛋白、脂肪前体细胞标记蛋白Myf5、线粒体合成调控蛋白NRF1、PPARγ和C/EBPα蛋白浓度显著低于对照组（P<0.05）。另外，RG1组BAT发育调控基因C/EBPα、PGC-1α、BMP7、BMP4、PPARγ显著低于CG组（P<0.05），而瘦素显著高于CG组（P<0.05）。转录组结果表明：各组胎儿肾周脂肪增殖和线粒体生物合成相关的信号通路主要富集在PI3K-Akt signaling pathway，mTOR signaling pathway，MAPK signaling pathway等。这些结果一定程度揭示了IUGR蒙古绵羊胎儿肾周脂肪线粒体生物合成程序化改变及其阻滞褐色脂肪细胞发育分化分子机理研究，为建立北方草原地区冬春季节合理科学的饲养管理制度以及医学该领域的研究提供一定的参考依据。