Skip to main content
. Author manuscript; available in PMC: 2021 Sep 8.
Published in final edited form as: Nat Metab. 2021 Mar 8;3(3):378–393. doi: 10.1038/s42255-021-00359-x

Fig. 7. A model for the coordinated regulation of glucose uptake and energy expenditure.

Fig. 7.

Insulin acts through a phosphaditylinositol-3-kinase -independent pathway to stimulate site-specific TUG cleavage, which is mediated by the Usp25m protease. Cleavage releases GLUT4 from the Golgi matrix. The N-terminal cleavage product, TUGUL, facilitates GLUT4 translocation to the plasma membrane by linking it to kinesin motors. The TUG C-terminal cleavage product is extracted from the Golgi matrix and enters the nucleus, where it binds PPARγ and PGC-1α. The TUG product stabilizes a complex containing these proteins, which activates the transcription of genes, including sarcolipin and Ucp1, that promote oxidative metabolism and thermogenesis. This action of the TUG C-terminal product is terminated by an Ate1-dependent degradation pathway, which limits the duration of the thermogenic effect.