To fulfill their function, pancreatic beta cells require precise nutrient-sensing mechanisms that control insulin production. Transcription factor EB (TFEB) and its homolog TFE3 have emerged as crucial regulators of the adaptive response of cell metabolism to environmental cues. Here, we show that TFEB and TFE3 regulate beta-cell function and insulin gene expression in response to variations in nutrient availability. We found that nutrient deprivation in beta cells promoted TFEB/TFE3 activation, which resulted in suppression of insulin gene expression. TFEB overexpression was sufficient to inhibit insulin transcription, whereas beta cells depleted of both TFEB and TFE3 failed to suppress insulin gene expression in response to amino acid deprivation. Interestingly, ChIP-seq analysis showed binding of TFEB to super-enhancer regions that regulate insulin transcription. Conditional, beta-cell-specific, Tfeb-overexpressing, and Tfeb/Tfe3 double-KO mice showed severe alteration of insulin transcription, secretion, and glucose tolerance, indicating that TFEB and TFE3 are important physiological mediators of pancreatic function. Our findings reveal a nutrient-controlled transcriptional mechanism that regulates insulin production, thus playing a key role in glucose homeostasis at both cellular and organismal levels.

中文翻译：

---

TFEB 和 TFE3 通过调节胰岛素基因表达来控制葡萄糖稳态

为了实现其功能，胰腺β细胞需要精确的营养感应机制来控制胰岛素的产生。转录因子 EB (TFEB) 及其同源物 TFE3 已成为细胞代谢对环境线索的适应性反应的关键调节因子。在这里，我们证明 TFEB 和 TFE3 调节 β 细胞功能和胰岛素基因表达，以响应营养可用性的变化。我们发现β细胞中的营养缺乏促进了TFEB/TFE3的激活，从而导致胰岛素基因表达的抑制。TFEB 过表达足以抑制胰岛素转录，而同时耗尽 TFEB 和 TFE3 的 β 细胞则无法抑制氨基酸剥夺时的胰岛素基因表达。有趣的是，ChIP-seq 分析显示 TFEB 与调节胰岛素转录的超级增强子区域结合。条件性、β细胞特异性、Tfeb过表达和Tfeb / Tfe3双KO小鼠表现出胰岛素转录、分泌和葡萄糖耐量的严重改变，表明TFEB和TFE3是胰腺功能的重要生理介质。我们的研究结果揭示了一种营养控制的转录机制，可调节胰岛素的产生，从而在细胞和有机体水平的葡萄糖稳态中发挥关键作用。