An insulin-stimulated proteolytic mechanism links energy expenditure with glucose uptake
| Autor: | Estifanos N. Habtemichael, Diana M. Ruiz, Daming Li, Bhavesh S. Sayal, Camporez Jp, Wang Ky, Henry Li, Sandro M. Hirabara, Xinran Liu, Daniel F. Vatner, Chloe I. Sales, Stephen G. DeVries, Gerald I. Shulman, William M. Philbrick, Francesc López-Giráldez, Xavier O. Westergaard, Jonathan S. Bogan |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Diabetes risk biology Chemistry Arginyltransferase Insulin medicine.medical_treatment Glucose uptake Glucose transporter Cleavage (embryo) Cell biology 03 medical and health sciences 0302 clinical medicine medicine biology.protein Specific dynamic action human activities 030217 neurology & neurosurgery GLUT4 030304 developmental biology |
| DOI: | 10.1101/817049 |
| Popis: | SummaryMechanisms to coordinately regulate energy expenditure and glucose uptake into muscle and fat cells are not well described. Insulin stimulates glucose uptake in part by causing site-specific endoproteolytic cleavage of TUG, which mobilizes GLUT4 glucose transporters to the cell surface. Here, we show that the TUG C-terminal cleavage product enters the nucleus, binds the transcriptional regulators PGC-1α and PPARγ, and increases oxidative metabolism and thermogenic protein expression. Muscle-specific genetic manipulation of this pathway impacts whole-body energy expenditure, independent of glucose uptake. The PPARγ2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The TUG cleavage product stabilizes PGC-1α and is itself susceptible to an Ate1 arginyltransferase -dependent degradation mechanism; binding of the TUG product confers Ate1-dependent stability upon PGC-1α. We conclude that TUG cleavage coordinates energy expenditure with glucose uptake, that this pathway may contribute to the thermic effect of food, and that its attenuation may be important in obesity. |
| Databáze: | OpenAIRE |
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