甜菜碱调控PPARα-Fgf21信号通路在妊娠期糖尿病致子代异常的作用和机制研究

The poor developmental environment in early life (maternal Gestational Diabetes Mellitus, GDM) can introduce "metabolic memory" to the fetus, resulting in a significant increased risk of metabolic disease in adulthood of offspring. The epigenetic phenomenon of DNA methylation modification may be an important mechanism of "metabolic memory". Based on previous clinical studies, we found that the betaine content of GDM mothers and infants was lower than that of the control group. Betaine is known to have an effect on improving glycolipid metabolism, and its major signaling pathways include agonizing PPARα and upregulating FGF21. However, the mechanism of betaine in the intrauterine developmental environment affecting the metabolism of offspring in adulthood is not clear. It has been reported that the activation of PPARα in pregnant mice can affect the methylation of the Fgf21 gene in the offspring. Therefore, we propose a scientific hypothesis that betaine can stimulate PPARα during pregnancy, thus alter the methylation of Fgf21 gene in offspring, thereby improving the metabolic phenotype of offspring in adulthood. This study is based on the trans-generational mouse model of abnormal glucose and lipid metabolism that has been constructed by the research team to verify whether betaine intervention can improve the metabolism phenotype of offspring, whether it is through the PPARα-Fgf21 gene methylation pathway, and is expected to provide new idea and new target for early prevention of diabets.

生命早期的不良发育环境（包括妊娠期糖尿病，GDM）可以对胎儿产生“代谢记忆”，致子代成年期患代谢疾病的风险显著增加。DNA甲基化修饰这一表观遗传现象可能是“代谢记忆”的重要机制。我们前期临床研究发现，与对照组相比GDM母婴体内甜菜碱含量均较低。已有研究显示甜菜碱具有改善糖脂代谢的作用，其主要信号通路包括激动PPARα进而上调FGF21。然而宫内发育环境中甜菜碱如何影响子代成年期代谢及其机制尚不明确。据报道孕鼠体内PPARα的激动可以影响子代Fgf21基因甲基化的修饰。因此我们提出科学假说，宫内发育环境中甜菜碱可以激动PPARα改变子代Fgf21基因的甲基化修饰，进而改善子代成年期的代谢表型。本课题拟基于课题组已构建的糖脂代谢异常跨代小鼠模型，验证甜菜碱干预是否可以改善母子代谢表型，是否是通过PPARα-Fgf21基因甲基化通路发挥调控作用，以期为糖尿病的早期防治提供新思路、新靶点。

生命早期的不良发育环境（包括妊娠期糖尿病，GDM）可以对胎儿产生“代谢记忆”，致子代成年期患代谢疾病的风险显著增加。DNA甲基化修饰这一表观遗传现象可能是“代谢记忆”的重要机制。我们前期临床研究发现，与对照组相比GDM母婴体内甜菜碱含量均较低，然而宫内发育环境中甜菜碱如何影响子代成年期代谢及其机制尚不明确。本课题拟基于课题组已构建的糖脂代谢异常跨代小鼠模型，发现孕期干预甜菜碱可以改善母亲高脂所带来的子代成年期代谢异常，并发现以下可能的重要机制：（1）对子代肠道菌产生长期影响，甜菜碱干预持续性升高母代、4周与20周龄小鼠中肠道菌Romboutsia的相对丰度，从而影响子代成年期代谢；（2）发现甜菜碱可显著改善母代高脂饮食给子代成年期带来的胰岛素抵抗和肝脏脂肪变性，对F1子代4周的肝脏进行全基因组甲基化测序，发现甜菜碱组显著上调子代肝脏E3泛素连接酶NEDD4L基因甲基化水平。同时发现子代5周龄甜菜碱组子代小鼠肝脏的ULK1转录水平发生了上调。在体外水平，甜菜碱干预后自噬小体快速进入溶酶体的过程，可能是自噬激活的一种生物学特点。因此提示子代肝脏中NEDD4L的下降，蛋白泛素化水平下调，且ULK1的上升和自噬激活。本研究可能为解释宫内发育环境影响二型糖尿病的发生发展提供重要的理论基础。同时这些天然富甲基的代谢小分子作为改变甲基化修饰的干预手段，有望在生命早期水平上为有效防止T2DM的发生发展提供健康指导新策略。