TFEB and TFE3 Control Glucose Homeostasis by Regulating Insulin Gene Expression

Authors

Adrien Pasquier
Nunzia Pastore
Luca D'Orsi
Rita Colonna
Alessandra Esposito
Veronica Maffia
Rossella De Cegli
Margherita Mutarelli
Susanna Ambrosio
Gennaro Tufano
Antonio Grimaldi
Marcella Cesana
Davide Cacchiarelli
Nathalie Delalleau
Gennaro Napolitano
Andrea Ballabio

Publication Date

11-2-2023

Journal

The EMBO Journal

DOI

10.15252/embj.2023113928

PMID

37712288

PMCID

PMC10620765

PubMedCentral® Posted Date

9-15-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Autophagy, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Gene Expression, Glucose, Insulin, Lysosomes, beta cells, glucose homeostasis, insulin, mTORC1, TFEB Chromatin, Transcription & Genomics, Metabolism

Abstract

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.