ArticleNature metabolism2021
Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake.
Article in Nature metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 31 citations in OpenAlex.
- Effects of Glucagon-Like Peptide-1 Receptor Agonists (Mono and Combination Therapy) on Energy Expenditure: A Scoping Review.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2026Article
- Altered Molecular Regulation of TUG Is a Central Feature of Insulin-Resistant Human Adipose Tissue.Diabetes · 2026Article
- Deciphering Uncoupling Proteins in Cellular Homeostasis and Metabolic Health.International journal of biological sciences · 2026Review
- Article
- ASPL couples the assembly of stress granules with their VCP-mediated disassembly.Science advances · 2025Article
- GRK2-mediated phosphorylation and de-succinylation of PKM2 reduce macrophage glycolysis in rheumatoid arthritis.Acta pharmacologica Sinica · 2025Article
- Site-1 protease is a negative regulator of sarcolipin promoter activity.Communications biology · 2025Article
- TUG protein acts through a disordered region to organize the early secretory pathway.Nature communications · 2025Article
- UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.Nature immunology · 2024Article
- Sustained caloric restriction potentiates insulin action by activating prostacyclin synthase.Obesity (Silver Spring, Md.) · 2024Article
- UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.Research square · 2024Article
- Fibroblast Growth Factor 21: A Fascinating Perspective on the Regulation of Muscle Metabolism.International journal of molecular sciences · 2023Review
- The intracellular helical bundle of human glucose transporter GLUT4 is important for complex formation with ASPL.FEBS open bio · 2023Article
- Article
- Hypermetabolism in mice carrying a near complete human chromosome 21.bioRxiv : the preprint server for biology · 2023Article
- The effects of sucrose and arsenic on muscular insulin signaling pathways differ between the gastrocnemius and quadriceps muscles.Frontiers in endocrinology · 2023Article
- Inhibitors of RNA and protein synthesis cause Glut4 translocation and increase glucose uptake in adipocytes.Scientific reports · 2022Article
- Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis.Nature communications · 2022Article
- Epigenomic Changes after Acupuncture Treatment in Patients Suffering from Burnout.Complementary medicine research · 2022Observational
- Ubiquitin-like processing of TUG proteins as a mechanism to regulate glucose uptake and energy metabolism in fat and muscle.Frontiers in endocrinology · 2022Review
Corrections and comments
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Authors and funding
21 authors at 2 institutions in 3 countries.
Funding
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)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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.