Metabolic syndromes, including obesity, cause neuropathophysiological changes in the brain, resulting in cognitive deficits. Only a few studies explored the contribution of non-coding genes in these pathophysiologies. Recently, we identified obesity-linked circular RNAs (circRNA) by analyzing the brain cortices of high-fat-fed obese mice. In this study, we scrutinized a conserved and neuron-specific circRNA, circTshz2-2, which affects neuronal cell cycle and spatial memory in the brain. Transcriptomic and cellular analysis indicated that circTshz2-2 dysregulation altered the expression of cell division-related genes and induced cell cycle arrest at the G2/M phase of the neuron. We found that circTshz2-2 bound to the YY1 transcriptional complex and suppressed Bdnf transcription. Suppression of circTshz2-2 increased BDNF expression and reduced G2/M checkpoint proteins such as Cyclin B2 and CDK1 through BDNF/TrkB signaling pathway, resulting in cell cycle arrest and neurite elongation. Inversely, overexpression of circTshz2-2 decreased BDNF expression, induced cell cycle proteins, and shortened the neurite length, indicating that circTshz2-2 regulates neuronal cell cycle and structure. Finally, we showed that circTshz2-2 affects spatial memory in wild-type and obese mice. Our data have revealed potential regulatory roles of obesity-related circTshz2-2 on the neuronal cell cycle and memory function providing a novel link between metabolic syndromes and cognitive deficits.

包括肥胖在内的代谢综合征会引起大脑的神经病理生理变化，从而导致认知缺陷。只有少数研究探讨了非编码基因在这些病理生理学中的作用。最近，我们通过分析高脂喂养的肥胖小鼠的大脑皮层，鉴定出与肥胖相关的环状 RNA (circRNA)。在这项研究中，我们仔细研究了一种保守的神经元特异性 circRNA，即 circTshz2-2，它影响大脑中的神经元细胞周期和空间记忆。转录组和细胞分析表明，circTshz2-2 失调改变了细胞分裂相关基因的表达，并在神经元的 G2/M 期诱导细胞周期停滞。我们发现 circTshz2-2 与 YY1 转录复合物结合并抑制Bdnf转录。抑制 circTshz2-2 通过 BDNF/TrkB 信号通路增加 BDNF 表达并减少 G2/M 检查点蛋白如 Cyclin B2 和 CDK1，导致细胞周期停滞和神经突伸长。相反，circTshz2-2的过表达会降低BDNF的表达，诱导细胞周期蛋白，缩短神经突长度，表明circTshz2-2调节神经元细胞周期和结构。最后，我们发现 circTshz2-2 影响野生型和肥胖小鼠的空间记忆。我们的数据揭示了肥胖相关的 circTshz2-2 对神经元细胞周期和记忆功能的潜在调节作用，提供了代谢综合征和认知缺陷之间的新联系。