饱和脂肪酸对胚胎神经系统发育的影响及机制研究

Previous studies have suggested that pregnancy obesity may alter brain structure in the offspring. However, the underlying mechanism is still unclear. Obesity is often marked by elevated free fatty acid levels, especially saturated fatty acids (SFAs), which play an important role in brain injury. Our preliminary data showed that, the proliferation of neural stem cells (NSCs) was decreased in fetuses from mothers fed the high SFAs diet when compared to controls. Furthermore, along with the abnormal proliferation and differentiation of the mouse embryonic NSCs in vitro, the level of Notch1 mRNA was also downregulated after SFAs treatment. These data suggested that SFAs played a role in neurogenesis through Notch passway and affected the development of embryonic nervous system. To verify the hypothesis, further studies should be carried out to investigate the effects of SFAs on the development of embryonic nervous system using high SFAs diet-induced pregnancy obesity modle; the effects of SFAs on the proliferation and differentiation of NSCs in vivo and in vitro; the role of Notch pathway in the effects of SFAs on neurogenesis using gene transfection and small interfering RNA. The study may further understanding of the mechanism of the negative effect of pregnancy obesity on the development of embryonic nervous system and provide a new strategy for clinical treatments.

孕期肥胖可引起子代神经系统发育异常，其发生机理至今尚不清楚。肥胖患者常伴有游离脂肪酸水平长期升高，其中饱和脂肪酸（SFAs）与神经系统功能损伤密切相关。我们在预实验中发现，高SFAs饮食性肥胖孕鼠组的胚鼠神经干细胞（NSCs）增殖明显低于正常饮食组。另外，SFAs引起原代培养的小鼠胚胎NSCs增殖分化异常，并下调Notch1 mRNA的表达。上述结果提示，SFAs可能是通过Notch信号通路调控NSCs的增殖分化，进而导致胚胎神经系统发育异常。为验证该假设，拟建立高SFAs饮食性肥胖动物模型，系统研究SFAs对胎鼠神经系统发育的影响；利用免疫荧光、蛋白印迹等方法检测SFAs对在体及离体NSCs增殖、分化的影响；利用基因转染、小干扰RNA等方法，检测Notch信号通路在SFAs调节NSCs增殖分化中的作用。通过上述研究，可为深入理解孕期肥胖致胚胎神经损伤的发病机理和治疗提供理论依据。

期肥胖包括孕前肥胖和孕期体重过度增加，可导致胎儿先天畸形、巨大儿、流产、难产和死胎等。在诸多先天畸形中以神经管畸形（包括露脑、颅脊柱裂、脊柱裂）最为常见。另外，追踪研究发现，肥胖孕妇所生外观未见异常的部分新生儿在成长过程中存在脑发育延迟的现象，表现为注意力不集中，消极情绪，智力水平低于正常及精神分裂等，并且注意缺陷多动障碍的发生率增加，提示肥胖孕妇的子代在胚胎期存在着不同程度的中枢神经发育异常，其发生机理至今尚不清楚。肥胖患者常伴有游离脂肪酸水平长期升高，其中饱和脂肪酸（saturated fatty acids, SFAs）与神经系统功能损伤密切相关。我们设想SFAs可能调控神经干细胞（neural stem cells, NSCs）的增殖分化，进而导致胚胎神经系统发育异常。我们在实验中发现，棕榈酸（paltimic acid, PA）（十六碳饱和脂肪酸）抑制原代培养的小鼠胚胎NSCs的存活，并表现出一定的剂量依赖性。PA抑制NSCs的增殖，并促进氧自由基（reactive oxygen species, ROS）的生成。进一步研究发现，PA可促进NSCs向神经胶质细胞的分化，对神经元的分化没有影响。同时我们还发现PA能调节NSCs分化相关基因的表达，比如下调Mas mRNA和 Ngn1 mRNA的表达，上调Notch mRNA和Hes1的mRNA的表达。以上结果提示SFAs影响了NSCs的有序的增殖及分化过程，导致了神经发育异常。该研究结果为深入研究孕期肥胖致胚胎神经损伤的发病机理和治疗方法提供依据。