Lin Cheng, Lin YanYan, Luo Ji, Yu JunRu, Cheng YaNi, Wu XiaoYun, Lin Lin, Lin YuanShao
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Endocrinology. 2021 Jan 1;162(1). doi: 10.1210/endocr/bqaa214.
As advances are made in the field of developmental origins of health and disease, there is an emphasis on long-term influence of maternal environmental factors on offspring health. Maternal high-fat diet (HFD) consumption has been suggested to exert detrimental effects on cognitive function in offspring, but whether HFD-dependent brain remodeling can be transmitted to the next generations is still unclear. This study tested the hypothesis that HFD consumption during rat pregnancy and lactation multigenerationally influences male offspring hippocampal synaptic plasticity and cognitive function. We observed that hippocampus-dependent learning and memory was impaired in 3 generations from HFD-fed maternal ancestors (referred as F1-F3), as assessed by novel object recognition and Morris water maze tests. Moreover, maternal HFD exposure also affected electrophysiological and ultrastructure measures of hippocampal synaptic plasticity across generations. We observed that intranasal insulin replacement partially rescued hippocampal synaptic plasticity and cognitive deficits in F3 rats, suggesting central insulin resistance may play an important role in maternal diet-induced neuroplasticity impairment. Furthermore, maternal HFD exposure enhanced the palmitoylation of GluA1 critically involved in long-term potentiation induction, while palmitoylation inhibitor 2-bromopalmitate counteracts GluA1 hyperpalmitoylation and partially abolishes the detrimental effects of maternal diet on learning and memory in F3 offspring. Importantly, maternal HFD-dependent GluA1 hyperpalmitoylation was reversed by insulin replacement. Taken together, our data suggest that maternal HFD exposure multigenerationally influences adult male offspring hippocampal synaptic plasticity and cognitive performance, and central insulin resistance may serve as the cross-talk between maternal diet and cognitive impairment across generations.
随着健康与疾病的发育起源领域取得进展，人们开始重视母体环境因素对后代健康的长期影响。有研究表明，母体高脂饮食（HFD）的摄入会对后代的认知功能产生不利影响，但尚不清楚依赖于HFD的大脑重塑是否会传递给下一代。本研究检验了这样一个假设，即大鼠怀孕和哺乳期的HFD摄入会多代影响雄性后代的海马突触可塑性和认知功能。通过新物体识别和莫里斯水迷宫测试评估，我们观察到来自喂食HFD的母系祖先的三代（称为F1 - F3）中，依赖海马的学习和记忆能力受损。此外，母体HFD暴露还会跨代影响海马突触可塑性的电生理和超微结构指标。我们观察到，鼻内注射胰岛素替代疗法部分挽救了F3大鼠的海马突触可塑性和认知缺陷，这表明中枢胰岛素抵抗可能在母体饮食诱导的神经可塑性损伤中起重要作用。此外，母体HFD暴露增强了在长时程增强诱导中起关键作用的GluA1的棕榈酰化，而棕榈酰化抑制剂2 - 溴棕榈酸可抵消GluA1的过度棕榈酰化，并部分消除母体饮食对F3后代学习和记忆的有害影响。重要的是，胰岛素替代可逆转母体HFD依赖的GluA1过度棕榈酰化。综上所述，我们的数据表明，母体HFD暴露会多代影响成年雄性后代的海马突触可塑性和认知表现，中枢胰岛素抵抗可能是母体饮食与跨代认知障碍之间的交互作用机制。
