Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2

Abstract

Objective: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis. However, the role of endothelial TFEB in metabolism remains to be explored. In this study, we sought to investigate the role of endothelial TFEB in glucose metabolism and underlying molecular mechanisms. Approach and Results: To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout and EC-selective TFEB transgenic mice fed a high-fat diet. EC-selective TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-selective TFEB transgenic mice showed improved glucose tolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts Akt (AKT serine/threonine kinase) signaling. Adenovirus-mediated overexpression of TFEB consistently activates Akt and significantly increases glucose uptake in ECs. Mechanistically, TFEB upregulates IRS1 and IRS2 (insulin receptor substrate 1 and 2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495, and miR-548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-selective TFEB knockout mice and consistently improved in EC-selective TFEB transgenic mice on high-fat diet. Conclusions: Our data revealed a critical role of TFEB in endothelial metabolism and suggest that TFEB constitutes a potential molecular target for the treatment of vascular and metabolic diseases.

TFEB Biology and Agonists at a Glance

“…It culminates in the activation of TFEB to enhance lysosomal biogenesis which is necessary for proper bone resorption [45]. Endothelial TFEB promotes glucose metabolism via upregulation of Insulin Receptor Substrate 1 and Insulin Receptor Substrate 2 [46]. TFEB plays an important role in resisting intestinal epithelial cell injury in vivo, potentially mediated by APOA1 [47].…”

The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases

“…As for glucose metabolism, TFEB can control the expressions of glucose transporters, glycolytic enzymes and glucose homeostasis pathways ( Mansueto et al, 2017 ). And glucose uptake can be increased by TFEB in ways of activating AKT and upregulating insulin receptor substrate 1 (IRS1) and IRS2 ( Sun et al, 2021 ).…”

Curcumin Derivative MTH-3 Regulates Palmitate-induced Insulin Resistance in Mouse Myoblast C2C12Cells

“…In the liver, TFEB regulates genes involved in lipid catabolism, fatty acid oxidation, and ketone synthesis (27). TFEB also plays a key role in mediating insulin sensitivity, glucose stabilization, lipid oxidation, and mitochondrial function (28). C 2 C 12 cells were treated with 5 and 10 μM MTH-3 in the absence or presence of PA (400 μM) for 24 h, and RNA was subsequently extracted.…”