State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of life Science and Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu province, P. R. China.
Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, China.
Nat Commun. 2023 Jan 21;14(1):351. doi: 10.1038/s41467-023-35998-z.
Pancreatic β-cell compensation is a major mechanism in delaying T2DM progression. Here we report the abnormal high expression of circGlis3 in islets of male mice with obesity and serum of people with obesity. Increasing circGlis3 is regulated by Quaking (QKI)-mediated splicing circularization. circGlis3 overexpression enhances insulin secretion and inhibits obesity-induced apoptosis in vitro and in vivo. Mechanistically, circGlis3 promotes insulin secretion by up-regulating NeuroD1 and Creb1 via sponging miR-124-3p and decreases apoptosis via interacting with the pro-apoptotic factor SCOTIN. The RNA binding protein FUS recruits circGlis3 and collectively assemble abnormal stable cytoplasmic stress granules (SG) in response to cellular stress. These findings highlight a physiological role for circRNAs in β-cell compensation and indicate that modulation of circGlis3 expression may represent a potential strategy to prevent β-cell dysfunction and apoptosis after obesity.
胰岛β细胞代偿是延迟 T2DM 进展的主要机制。在这里，我们报道了肥胖男性小鼠胰岛和肥胖人群血清中 circGlis3 的异常高表达。circGlis3 的增加受到 Quaking（QKI）介导的剪接环化调控。circGlis3 的过表达增强了体外和体内胰岛素的分泌，并抑制了肥胖诱导的细胞凋亡。在机制上，circGlis3 通过海绵吸附 miR-124-3p 而上调 NeuroD1 和 Creb1 促进胰岛素分泌，并通过与促凋亡因子 SCOTIN 相互作用减少凋亡。RNA 结合蛋白 FUS 募集 circGlis3，并在细胞应激时共同组装异常稳定的细胞质应激颗粒 (SG)。这些发现强调了 circRNAs 在β细胞代偿中的生理作用，并表明调节 circGlis3 的表达可能代表一种预防肥胖后β细胞功能障碍和细胞凋亡的潜在策略。
