Estifanos N Habtemichael, Don T Li, João Paulo Camporez, Xavier O Westergaard, Chloe I Sales, Xinran Liu, Francesc López-Giráldez, Stephen G DeVries, Hanbing Li, Diana M Ruiz, Kenny Y Wang, Bhavesh S Sayal, Sofia González Zapata, Pamela Dann, Stacey N Brown, Sandro Hirabara, Daniel F Vatner, Leigh Goedeke, William Philbrick, Gerald I Shulman, Jonathan S Bogan
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...
March 8, 2021: Nature metabolism