从下丘脑代谢编程探讨围产期母亲肥胖对子代影响的分子机制及干预对策

围产期母亲肥胖能增加后代患肥胖的风险；下丘脑是能量调控的神经中枢，其富含的代谢性核受体控制着摄食调节肽的产生。代谢性核受体-摄食调节肽通路的紊乱系肥胖形成的关键环节。围产期的母亲肥胖是否及如何影响子代下丘脑摄食调节，目前尚不明确。本课题拟利用高脂饮食诱发的雌性大鼠肥胖模型，观察围产期肥胖对子代代谢器官的形态结构、生物表型、表观遗传特征和基因表达模式的影响。通过甲基化DNA免疫共沉淀结合测序技术、亚硫酸盐测序等表观遗传学的研究手段，探讨围产期母亲肥胖对子代下丘脑代谢性核受体基因启动子甲基化修饰模式的影响及其对关键摄食调节肽的调控，并在全基因组范围内筛选和确认其他重要效应分子启动子的甲基化修饰图谱，以期阐明围产期的母亲肥胖产生跨代影响的机制，为围产期肥胖所致不良结局的干预提供科学依据。本研究有望打破肥胖在“母亲-子代-母亲”间的恶性循环，对从源头上控制肥胖的发生和发展，有重要的应用价值。

This project essentially aims to determine the underlying pathophysiology of maternal obesity during perinatal period, its modulations on the parameters of neonatal growth/development and metabolic health of the offspring, and to throw some light on the novel management approaches which can complement as well as improve the existing clinical regimen. The main contents of the research project are as follows: by using high fat diet induced obese pregnant rat models with measurement of relevent parameters in the neonate and post-pubertal offspring, we aim (1) to determine whether maternal obesity during perinatal period affects the metabolic phenotypes in the offspring; (2) to identify key changes in hypothalamic orexigenic (NPY)/anorexigenic (POMC) peptides; (3) to determine whether metabolic nuclear receptors (mainly RXRα and PPARγ) modulate the hypothalamic neuropeptides; (4) to explore the epigenetic mechanisms of metabolic malprogramming in controlling the hypothalamic feeding circuits; and (5) to delineate the role of maternal obesity and obesity-associated inflammation in epigenetic mechanisms of metabolic malprogramming. The studies may be translated into humans and will be beneficial to our understanding the molecular mechanism of transgenerational consequences of maternal obesity and possibly provide for a novel potential preventive target for obese epidemic. Our study highlights the importance of managing maternal body weight during pregnancy on the mother, infant and child for preventing the obesity in the later life.