The circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis during obesity

Abstract The molecular link between obesity and β-cell decompensation that causes diabetes remains incompletely understood. Here we found that circGlis3, a circular RNA derived from Glis3, plays a critical role in islet β-cell compensation. circGlis3 was increased in islets of obese mouse models and moderately diabetic individuals with compensated β-cell function by Quaking (QKI)-mediated splicing. Overexpression of circGlis3 functions to restrain islet β-cell dysfunction and maintain β-cell mass in high-fat diet (HFD) fed mice and Leprdb/db mice. The cellular levels of circGlis3 modulate both insulin synthesis and secretion and lipotoxicity-induced apoptosis, resulting in profound changes in β-cell compensation. In an obesity model, circGlis3 promotes the synthesis and secretion of insulin by upregulating NeuroD1 and Creb1 through sponging miR-124-3p. In addition, we identified SCOTIN and fused in sarcoma (FUS) as interacting proteins using quantitative mass spectrometry. We demonstrated that the binding of SCOTIN to circGlis3 regulated the apoptosis of β-cell. And more, FUS binding to circGlis3 could decrease free circGlis3 in cytoplasm and block mechanism of circGlis3 via abnormal stable formation of stress granules (SGs) in hyperactive response to chronic stresses in obesity that is thought to contribute to the β-cell decompensation. These findings highlight a physiological role for circRNAs in compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to protect against islet β-cell dysfunction and apoptosis during obesity.