Abstract：
Environmental factors in early life have been demonstrated to increase the risk of neurodevelopmental disorders in offspring, especially the deficiency of the cognitive ability. Leptin has emerged as a key hormone that conveys information on energy stores, but there is growing appreciation that leptin signaling may also play an important role in neurodevelopment. The present study aimed to investigate whether maternal HFD exposure impairs the offspring learning and memory through the programming of central leptin system. We observed that hippocampus-dependent learning and memory were impaired in male but not female offspring from HFD-fed maternal ancestors (C57BL/6 mice), as assessed by novel object recognition and Morris water maze tests. Moreover, the chromatin immunoprecipitation results revealed the maternal HFD consumption led to the increasement in the binding of the histone marker H3K9me3 in male offspring, which mediates gene silencing in the leptin receptor promoter region. Furthermore, there was an increase in the expression of the histone methylase SUV39H1 in male but not female offspring, which regulates H3K9me3. Additionally, it has been observed that IL-6 and IL-1 also could lead to similar alternations when acting on cultured hippocampal neurons in vitro. Taken together, our data suggest that maternal HFD consumption influences male offspring hippocampal cognitive performance in a sex-specific manner, and central leptin signaling may serve as the cross-talk between maternal diet and cognitive impairment in offspring.
摘要：
已经证明生命早期的环境因素会增加后代神经发育障碍的风险，尤其是认知能力的不足。瘦素已经成为一种关键的激素，可以传达能量储存的信息，但是越来越多的人认识到瘦素信号在神经发育中也起着重要作用。本研究旨在探讨母体HFD暴露是否通过中枢瘦素系统的编程来损害后代的学习和记忆。我们观察到海马依赖的学习和记忆在HFD喂养的母系祖先（C57BL/6小鼠）的雄性后代中受损，而不是雌性后代。通过新颖的物体识别和莫里斯水迷宫测试进行评估。此外，染色质免疫沉淀结果显示，母体HFD的消耗导致雄性后代中组蛋白标记H3K9me3的结合增加，介导瘦素受体启动子区的基因沉默。此外，组蛋白甲基化酶SUV39H1的表达在雄性而不是雌性后代中增加，调节H3K9me3。此外,已经观察到,当在体外作用于培养的海马神经元时,IL-6和IL-1也可以导致类似的变化。一起来看,我们的数据表明，母体HFD消耗以性别特异性方式影响雄性后代海马认知表现，和中枢瘦素信号可能是母亲饮食和后代认知障碍之间的交叉对话。
