Biology subjects

Li, D. T.

Publications and source records attributed to Li, D. T..

2 recordsLinked to original sources

bioRxiv2025

High-fat diet ablates an insulin-responsive pool of GLUT4 glucose transporters in skeletal muscle

To stimulate glucose uptake in muscle, insulin mobilizes GLUT4 glucose transporters to the cell surface. During fasting, GLUT4 and the transmembrane aminopeptidase IRAP are trapped in intracellular, insulin-responsive vesicles bound by TUG, AS160, and Usp25m proteins. Here we show that Usp25m, a protease, is required for the bulk of insulin-stimulated TUG cleavage and consequent vesicle mobilization and glucose uptake. Efficient TUG cleavage also requires AS160. In mice with diet-induced insulin resistance, Usp25m abundance is reduced, IRAP is mislocalized during fasting, and TUG cleavage is impaired; effects of Usp25m and TUG deletion to alter insulin-stimulated and fasting glucose uptake, respectively, are ablated. We conclude that skeletal muscle insulin resistance results in part from altered membrane trafficking of GLUT4 and IRAP during fasting. This alteration depletes the pool of insulin-responsive vesicles marked by TUG and Usp25m. Mistargeting of GLUT4 and IRAP may contribute to distinct aspects of the metabolic syndrome in humans.

physiology↗

bioRxiv2019

An insulin-stimulated proteolytic mechanism links energy expenditure with glucose uptake

Mechanisms 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-1 and PPAR{gamma}, 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 PPAR{gamma}2 Pro12Ala polymorphism, which reduces diabetes risk, enhances TUG binding. The TUG cleavage product stabilizes PGC-1 and is itself susceptible to an Ate1 arginyltransferase -dependent degradation mechanism; binding of the TUG product confers Ate1-dependent stability upon PGC-1. 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.

physiology↗