Niu Yan, Chang Pan, Liu Tian, Shen Xi, Zhao Hui, Zhang Mingxia, Lei Shengping, Chen Baoying, Yu Jun
Clinical Experimental Center, Xi'an International Medical Center Hospital, Xi'an, China.
Department of Cardiology, The Second Affiliated Hospital, Xi'an Medical University, Xi'an, China.
Front Mol Neurosci. 2022 Oct 3;15:1000482. doi: 10.3389/fnmol.2022.1000482. eCollection 2022.
Obesity induced by a high-fat diet (HFD) is an important cause of impaired memory and cognitive function, but the underlying mechanisms are not clear. In the present study, we analyzed the levels of circRNAs in the hippocampus of C57BL/6J mice and evaluated the memory and cognition ability of C57BL/6J mice with HFD using Morris water maze and Y-maze approaches to explore the potential mechanisms linking circRNAs in obesity-associated cognitive impairment. Learning performance showed that HFD-induced obesity mice have impaired memory and cognition. The Arraystar analysis of the hippocampus displayed that HFD-induced obesity leads to the differential expression of circRNAs (DE-circRNAs) in mice. In total, 46 circular RNAs with elevated expression and 10 with decreased expression were identified. Among them, mmu_circRNA_004797 was identified to be significantly downregulated and the expression of mmu_circRNA_21040 was significantly upregulated in the HFD-fed mice, compared with control mice by PCR test. Bioinformatics analysis also showed that the upregulated circRNAs were related to the neuronal function and behavior, and material transport process, while downregulated circRNAs participated in the process of cell response to external stimuli, such as cellular response to nutrient levels. Furthermore, the KEGG pathway analysis showed that the upregulated circRNAs are mainly involved in Axon guidance, calcium signaling pathway, and ErbB signaling pathway. Only a single significant pathway, that is, "protein processing in endoplasmic reticulum", was observed in the downregulated circRNAs. Finally, we examined the deficits of hippocampal synaptic plasticity and detected the expression of ER stress-related protein. The results showed that ER stress was activated in the hippocampus, and hippocampal synaptic plasticity deficits were displayed. Our results demonstrated that circRNAs were most likely implicated in the predisposition to obesity-associated cognitive impairment.
高脂饮食（HFD）诱导的肥胖是记忆和认知功能受损的重要原因，但其潜在机制尚不清楚。在本研究中，我们分析了C57BL/6J小鼠海马中环状RNA（circRNAs）的水平，并使用Morris水迷宫和Y迷宫方法评估了HFD喂养的C57BL/6J小鼠的记忆和认知能力，以探索circRNAs在肥胖相关认知障碍中的潜在机制。学习表现表明，HFD诱导的肥胖小鼠存在记忆和认知障碍。对海马的Arraystar分析显示，HFD诱导的肥胖导致小鼠体内circRNAs（差异表达环状RNA，DE-circRNAs）的表达差异。总共鉴定出46种表达上调的环状RNA和10种表达下调的环状RNA。其中，通过PCR检测发现，与对照小鼠相比，HFD喂养小鼠中mmu_circRNA_004797显著下调，mmu_circRNA_21040的表达显著上调。生物信息学分析还表明，上调的circRNAs与神经元功能和行为以及物质运输过程有关，而下调的circRNAs参与细胞对外界刺激的反应过程，如细胞对营养水平的反应。此外，KEGG通路分析表明，上调 的circRNAs主要参与轴突导向、钙信号通路和ErbB信号通路。在下调的circRNAs中仅观察到一个显著的通路，即“内质网中的蛋白质加工”。最后，我们检查了海马突触可塑性的缺陷，并检测了内质网应激相关蛋白的表达。结果表明，海马中的内质网应激被激活，并且出现了海马突触可塑性缺陷。我们的结果表明，circRNAs很可能与肥胖相关认知障碍的易感性有关。
