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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.

Obesity-linked circular RNA circTshz2-2 regulates the neuronal cell cycle and spatial memory in the brain