Journal
NATURE METABOLISM
Volume 3, Issue 3, Pages 378-U153Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-021-00359-x
Keywords
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Categories
Funding
- NIH [P30 DK045735, R01 DK092661, R56 DK092661]
- American Diabetes Association [1-17-IBS-40]
- Yale DRC Pilot grant [P30 DK045735]
- Sao Paulo Research Foundation (FAPESP) [2018/04956-5]
- Natural Science Foundation of Zhejiang Province, China [LY18H070004]
- Brazilian Coordination for the Improvement of Higher Education Personnel [CAPES/PVEX88881.170862/2018-01]
- Postgraduate and Research Dean Award, Cruzeiro do Sul [PRPGP/UNICSUL-0708/2019]
- [R01 DK116774]
- [R01 DK114793]
- [T32 GM136651]
- [F30 DK115037]
- [R01 DK124272]
- [K99 HL150234]
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Insulin-stimulated TUG cleavage pathway regulates gene expression to promote lipid oxidation and thermogenesis, linking glucose uptake to organismal energy expenditure. Attenuation of this mechanism may promote obesity as it contributes to the thermic effect of food.
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.
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