Sestrin 3 Protein Enhances Hepatic Insulin Sensitivity by Direct Activation of the mTORC2-Akt Signaling

• DOI: 10.2337/db14-0539
• Publication Date: 2014-11-07T07:45:37Z
• Authors: Rongya Tao; Xiwen Xiong; Suthat Liangpunsakul; X. Charlie Dong
• Keywords: mTORC2; Knockout mouse; AMP-Activated Protein Kinase

Sestrin proteins have been implicated in multiple biological processes including resistance to oxidative and genotoxic stresses, protection against aging-related pathologies, promotion of metabolic homeostasis; however, the underlying mechanisms are incompletely understood. Some evidence suggests that sestrins may inhibit mTORC1 (mechanistic target rapamycin complex 1) through inhibition RagA/B GTPases or activation AMPK; whether also involved mTORC2 regulation function is unclear. To investigate functions 3 (Sesn3), we generated Sesn3 liver-specific transgenic knockout mice. Our data show mice exhibit insulin glucose intolerance, were protected induced by a high-fat diet. Using AMPK mice, demonstrate insulin-sensitizing effect largely independent AMPK. Biochemical analysis reveals interacts with activates subsequently stimulates Akt phosphorylation at Ser473. These findings suggest can activate via regulate hepatic sensitivity metabolism.