生命早期饥饿与成年饱食“两次打击”导致机体糖脂代谢感应网络重塑的机制研究

Malnutrition in early embryonic stage is closely related to adult metabolic diseases. Our previous study found that exposure to famine in early life and then overnutrition in adulthood ("two hits" nutrition imbalance) was significantly associated with glucose and lipid metabolism disorders; animal studies showed there was abnormal lipid accumulation in liver after two hits; and key enzymes of glycolipid metabolism and lncRNA regulating PPARa were significantly different, and pancreatic B7-H4 and JAM3 greatly increased. Therefore, the hypothesis is that PPARa is down-regulated after hunger in the early life, and the metabolism of glycolipids is weakened; adult overnutrition re-stresses and remodels the nutrition sensing network through regulating lncRNA. B7-H4 and JAM3 remodel the pancreatic function and reprogram the key enzymes of glycolipid metabolism. This project will use isotope tracing to explore the exact pathway of abnormal glucose and lipid metabolism, and clarify the remodeling and genetic mechanism of nutrient sensing network from multiple levels. We hope to carry out primary prevention of glucose and lipid metabolism disorders. With the progress of global urbanization, there are still 70.17 million poor people in rural China and people from many poor countries in Africa. They will also experience “two hits” on the nutritional life track, and they will be a big reservoir for diabetes. The study is important for maternal and child health and future adult health in developing countries.

胚胎早期饥饿与成年代谢疾病密切相关，我们前期研究发现华东地区自然人群生命早期饥饿继成年饱食（“两次打击”营养失衡）与糖脂代谢紊乱密切相关；动物研究显示两次打击后肝脂异常储积；糖脂代谢关键酶及调控PPARa的lncRNA差异显著，胰腺B7-H4及JAM3显著升高。因此提出假说，生命早期饥饿一次打击后PPARa下调，糖脂代谢能力减弱；成年过度饱食再次应激使糖脂代谢调控LncRNA等网络重建，B7-H4及JAM3重塑胰腺功能，调控重编程糖脂代谢关键酶表达并传代。项目采用同位素示踪探讨两次打击机体糖脂代谢异常的确切途径，从分子、细胞、机体多层次阐明营养感应网络重建重塑和遗传机制，希望进行糖脂代谢紊乱一级预防，随着全球城市化进展，中国农村尚有7017万贫困人口及非洲许多穷困国家的人群，他们也将进行“两次打击”营养生活轨迹,他们将是糖尿病强大后备军。该研究对发展中国家的母婴及未来成人健康有重要意义。

生命周期中正常营养是机体健康关键，我们前期2014年人群队列研究，发现胎儿及儿童期经历三年大饥荒后糖尿病风险上升90%，继成年后营养过剩进一步提高56%，2019年随访此人群，新发糖尿病和肥胖发病率明显增加，提出生命早期营养不足继成年后营养过剩“两次打击”营养失衡致糖脂代谢紊乱学说。“两次打击”人群多器官功能紊乱，动物模型多个代谢器官功能受损，以肝脏脂肪沉积最为明显。但其致病机理尚不明确，传代特点也不清楚。本项目利用同位素示踪研究“两次打击”导致糖脂代谢紊乱的病理特点，发现肝脏葡萄糖合成在“两次打击”大鼠异常升高，不管是皮下脂肪还是内脏脂肪，其脂肪细胞的直径明显变大，骨骼肌葡萄糖摄取能力较单纯高脂喂养大鼠显著下降。利用转录组学、代谢组学及、蛋白质及其修饰组学等多组学研究，揭示HSP90ab1-K284ac-LKB1-AMPK信号通路在两次打击营养感应网络重塑导致糖脂代谢紊乱中的重要作用，建立了两次打击子代模型，明确了两次打击导致糖脂代谢紊乱的传代特点，有望在脱贫致富年代为糖脂代谢紊乱性疾病的防治提供实验依据。