Our study aimed to elucidate the pathogenesis that predisposes to cognitive impairment after obesity.Ĭircular RNAs are defined as a kind of endogenous non-coding RNAs (ncRNAs) which are a group of RNAs generated during splicing with a covalently closed cyclic structure ( Kristensen et al., 2019). Thus, it is noteworthy that obesity-associated cognitive impairment has become increasingly serious, and may be an early manifestation of neurodegenerative diseases, which should be given high attention. Moreover, accumulating evidence indicates that obesity is a potential risk factor for many metabolic syndromes, including glucose intolerance, insulin resistance, hyperinsulinemia, dyslipidemia, nonalcoholic fatty liver disease, and type 2 diabetes ( Polyzos et al., 2019 Piché et al., 2020) These are closely related to the occurrence of cognitive dysfunction. It has been reported that obesity has many deleterious effects on the brain, including changes in endoplasmic reticulum stress, autophagy, oxidative stress, and inflammation reaction that are believed to promote neurological disease ( Alzoubi et al., 2018 Kong et al., 2018 Tan et al., 2018 Ye et al., 2018 Tan and Norhaizan, 2019). The high prevalence of obesity is one of the leading causes of elevated cognitive dysfunction. Obesity is a contributor to many adverse health outcomes, including increased risk for dementia and adverse structural and functional changes to multiple organs ( Vecchié et al., 2018 Zhang W. Obesity is defined as a complex chronic disease, caused by an imbalance between food intake and energy expenditure ( Pan et al., 2021). Obesity has become a pandemic in recent decades, having been considered to be undoubtedly one of the greatest public health challenges around the world. Our results demonstrated that circRNAs were most likely implicated in the predisposition to obesity-associated cognitive impairment. The results showed that ER stress was activated in the hippocampus, and hippocampal synaptic plasticity deficits were displayed. Finally, we examined the deficits of hippocampal synaptic plasticity and detected the expression of ER stress-related protein. Only a single significant pathway, that is, “protein processing in endoplasmic reticulum”, was observed in the downregulated circRNAs. Furthermore, the KEGG pathway analysis showed that the upregulated circRNAs are mainly involved in Axon guidance, calcium signaling pathway, and ErbB signaling pathway. 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. 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. In total, 46 circular RNAs with elevated expression and 10 with decreased expression were identified. The Arraystar analysis of the hippocampus displayed that HFD-induced obesity leads to the differential expression of circRNAs (DE-circRNAs) in mice. Learning performance showed that HFD-induced obesity mice have impaired memory and cognition. 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. 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.
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