Raptor determines beta-cell identity and plasticity independent of hyperglycemia in mice
Raptor determines beta-cell identity and plasticity independent of hyperglycemia in mice
复制标题
Raptor 确定与小鼠高血糖无关的 β 细胞身份和可塑性
DOI：
10.1038/s41467-020-15935-0
复制
发表时间：
2020
影响因子：
16.6
通讯作者：
Guang Ning
中科院分区：
文献类型：
--
作者：
Qinglei Yin;Qicheng Ni;Yichen Wang;Hongli Zhang;Wenyi Li;Aifang Nie;Shu Wang;Yanyun Gu;Qidi Wang;Guang Ning
受损的β细胞身份正在成为糖尿病中β细胞衰竭的重要因素;然而，独立于高血糖症的精确机制正在研究中。我们以前报道过mTORC 1/Raptor调节β细胞的功能成熟。在本研究中，我们发现糖尿病β细胞特异性Raptor缺陷小鼠（βRapKOGFP）表现出β细胞质量减少，β细胞身份丧失和α细胞特征获得;这些在葡萄糖正常化后是不可逆的。Raptor的缺失直接损害β细胞的特性、线粒体代谢偶联和蛋白质合成活性，导致β细胞衰竭。此外，Raptor基因的缺失激活了α细胞转录因子MafB（通过调节C/EBPβ亚型比例）和一些α细胞富集基因Etv 1和Tspan 12，从而启动了β细胞向α细胞的重编程。目前的研究结果强调mTORC 1作为代谢变阻器，用于稳定β细胞身份并在正常血糖水平下抑制α细胞程序，这可能为糖尿病的治疗提供治疗机会。
Compromised β-cell identity is emerging as an important contributor to β-cell failure in diabetes; however, the precise mechanism independent of hyperglycemia is under investigation. We have previously reported that mTORC1/Raptor regulates functional maturation in β-cells. In the present study, we find that diabetic β-cell specificRaptor-deficient mice (βRapKOGFP) show reduced β-cell mass, loss of β-cell identity and acquisition of α-cell features; which are not reversible upon glucose normalization. Deletion ofRaptordirectly impairs β-cell identity, mitochondrial metabolic coupling and protein synthetic activity, leading to β-cell failure. Moreover, loss ofRaptoractivates α-cell transcription factorMafB(via modulating C/EBPβ isoform ratio) and several α-cell enriched genes i.e.Etv1andTspan12, thus initiates β- to α-cell reprograming. The present findings highlight mTORC1 as a metabolic rheostat for stabilizing β-cell identity and repressing α-cell program at normoglycemic level, which might present therapeutic opportunities for treatment of diabetes.