Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake
| Autor: | Estifanos N. Habtemichael, Chloe I. Sales, Francesc López-Giráldez, Xavier O. Westergaard, Hanbing Li, Jonathan S. Bogan, Pamela Dann, Stephen G. DeVries, Don T. Li, Joao Paulo Camporez, Gerald I. Shulman, Stacey N. Brown, Sandro M. Hirabara, William M. Philbrick, Diana M. Ruiz, Xinran Liu, Bhavesh S. Sayal, Sofia González Zapata, Daniel F. Vatner, Kenny Y. Wang, Leigh Goedeke |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Diabetes risk
Arginyltransferase Endocrinology Diabetes and Metabolism Glucose uptake medicine.medical_treatment Article TERMOGÊNESE Mice Downregulation and upregulation Lipid oxidation Physiology (medical) 3T3-L1 Cells Internal Medicine medicine Animals Insulin Mice Knockout biology Chemistry Glucose transporter Intracellular Signaling Peptides and Proteins Thermogenesis Cell Biology Aminoacyltransferases Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology PPAR gamma Glucose Proteolysis biology.protein Energy Metabolism human activities Oxidation-Reduction GLUT4 |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Nature metabolism |
| Popis: | TUG tethering proteins bind and sequester GLUT4 glucose transporters intracellularly, and insulin stimulates TUG cleavage to translocate GLUT4 to the cell surface and increase glucose uptake. This effect of insulin is independent of phosphatidylinositol 3-kinase, and its physiological relevance remains uncertain. Here we show that this TUG cleavage pathway regulates both insulin-stimulated glucose uptake in muscle and organism-level energy expenditure. Using mice with muscle-specific Tug (Aspscr1)-knockout and muscle-specific constitutive TUG cleavage, we show that, after GLUT4 release, the TUG C-terminal cleavage product enters the nucleus, binds peroxisome proliferator-activated receptor (PPAR)γ and its coactivator PGC-1α and regulates gene expression to promote lipid oxidation and thermogenesis. This pathway acts in muscle and adipose cells to upregulate sarcolipin and uncoupling protein 1 (UCP1), respectively. The PPARγ2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The ATE1 arginyltransferase, which mediates a specific protein degradation pathway and controls thermogenesis, regulates the stability of the TUG product. We conclude that insulin-stimulated TUG cleavage coordinates whole-body energy expenditure with glucose uptake, that this mechanism might contribute to the thermic effect of food and that its attenuation could promote obesity. Insulin stimulates TUG cleavage to translocate GLUT4 and enhance glucose uptake. Here Bogan and colleagues show that the TUG cleavage product regulates thermogenic gene transcription, thereby coupling glucose uptake to organismal energy expenditure. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|