Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake

Author(s):Show less -

Habtemichael, Estifanos N. ^{[1, 2]} ; Li, Don T. ^{[1, 3]} ; Camporez, Joao Paulo ^{[4, 1]} ; Westergaard, Xavier O. ^{[5, 1]} ; Sales, I, Chloe ; Liu, Xinran ^[3] ; Lopez-Giraldez, Francesc ^[6] ; DeVries, Stephen G. ^[7] ; Li, Hanbing ^{[7, 8]} ; Ruiz, Diana M. ^[7] ; Wang, Kenny Y. ^[7] ; Sayal, Bhavesh S. ^[7] ; Zapata, Sofia Gonzalez ^[7] ; Dann, Pamela ^[7] ; Brown, Stacey N. ^[7] ; Hirabara, Sandro ^{[9, 7]} ; Vatner, Daniel F. ^[7] ; Goedeke, Leigh ^[7] ; Philbrick, William ^[7] ; Shulman, I, Gerald ; Bogan, Jonathan S. ^{[3, 10]}

Affiliation

^[1] Yale Sch Med, Dept Internal Med, Sect Endocrinol & Metab, New Haven, CT 06510 - USA

^[2] Evelo Biosci Inc, Cambridge, MA - USA

^[3] Yale Sch Med, Dept Cell Biol, New Haven, CT 06510 - USA

^[4] Univ Sao Paulo, Sao Paulo - Brazil

^[5] Columbia Univ, New York, NY - USA

^[6] Yale Sch Med, Yale Ctr Genome Anal, New Haven, CT - USA

^[7] Sales, Chloe, I, Yale Sch Med, Dept Internal Med, Sect Endocrinol & Metab, New Haven, CT 06510 - USA

^[8] Zhejiang Univ Technol, Hangzhou - Peoples R China

^[9] Cruzeiro do Sul Univ, Inst Phys Act Sci & Sports, Sao Paulo - Brazil

^[10] Shulman, Gerald, I, Sales, Chloe, I, Yale Sch Med, Dept Internal Med, Sect Endocrinol & Metab, New Haven, CT 06510 - USA

• Document type: Journal article
• Source: NATURE METABOLISM; v. 3, n. 3 MAR 2021.
• Web of Science Citations: 0

Abstract

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)gamma and its coactivator PGC-1 alpha 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 PPAR gamma 2 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. (AU)

• FAPESP's process: 18/04956-5 - Impact of the estrogen receptor alpha on Non-Alcoholic Fatty Liver Disease and energetic metabolism of the liver
• Grantee: João Paulo Gabriel Camporez
• Support Opportunities: Research Grants - Young Investigators Grants