Abstract

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.

Highlights

  • Countless people suffer from various diseases related to metabolic imbalances including obesity, diabetes mellitus, and hypertension [1]

  • Nine of the 15 circular RNAs (circRNA) are expressed in the neuron, suggesting that these obesity-related circRNAs play some critical roles in neuronal function

  • Our results suggest that circTshz2-2 regulates cell cycle arrest at the G2/M phase by regulating Cyclin B2/CDK1 and brain-derived neurotrophic factor (BDNF) expression

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Summary

INTRODUCTION

Countless people suffer from various diseases related to metabolic imbalances including obesity, diabetes mellitus, and hypertension [1]. Increased local and systemic inflammation following metabolic imbalance causes blood-brain barrier collapse and increases the infiltration of glucose, insulin, free fatty acid, and cholesterol into the brain [6] The imbalance of these factors manifests as insulin resistance and accelerates inflammatory responses in glial and neuronal cells, resulting in impaired synaptic plasticity, neuronal cell damage, and memory impairment [7]. The primary function of circRNAs has been described as the regulation of gene expression via microRNA sponging or RNA-binding protein sequestration [12]. CircHIPK3 has been described as a circTshz showed further increases in their expression after regulator of obesity-induced insulin resistance and is known to 3 days of differentiation (Supplementary Fig. S3B). No study has described the A few studies have reported functions for both circTshz and roles of these obesity-related circRNAs in neuronal differentiation, Tshz. Our previous RNA-seq data identified two isoforms of circTshz; circTshz and

RESULTS
DISCUSSION
14 REFERENCES
Yoon et al 15
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