1. Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1
- Author
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Camila Martinez Calejman, Danette L. Daniels, Su Myung Jung, David A. Guertin, Dimpi Mukhopadhyay, Barbara Martinez-Pastor, Amelia K. Luciano, Jivani M. Gengatharan, Huawei Li, Christian M. Metallo, Raul Mostoslavsky, Wen-Yu Hsiao, Chien-Min Hung, Samuel R. Hildebrand, Martina Wallace, Joan Sanchez-Gurmaches, and Yuefeng Tang
- Subjects
Lipolysis ,Mice, Transgenic ,FOXO1 ,Mechanistic Target of Rapamycin Complex 2 ,Biology ,mTORC2 ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Adipocyte ,Brown adipose tissue ,medicine ,Animals ,Humans ,Sirtuins ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,0303 health sciences ,Forkhead Box Protein O1 ,Kinase ,Lipid metabolism ,Cell Biology ,Cell biology ,Adipocytes, Brown ,HEK293 Cells ,Rapamycin-Insensitive Companion of mTOR Protein ,medicine.anatomical_structure ,chemistry ,lipids (amino acids, peptides, and proteins) ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
mTORC2 controls glucose and lipid metabolism, but the mechanisms have been unclear. Here, we show that conditionally deleting the essential mTORC2 subunit Rictor in murine brown adipocytes inhibits de novo lipid synthesis, promotes lipid catabolism and thermogenesis, and protects against diet-induced obesity and hepatic steatosis. AKT kinases are the canonical mTORC2 substrates; however, deleting Rictor in brown adipocytes appears to drive lipid catabolism by promoting FoxO1 deacetylation independently of AKT and SGK, and in a pathway distinct from its positive role in anabolic lipid synthesis. This facilitates FoxO1 nuclear retention, enhances lipid uptake and lipolysis, and potentiates UCP1 expression. We provide evidence that SIRT6 is the FoxO1 deacetylase suppressed by mTORC2, and show an endogenous interaction between SIRT6 and mTORC2 in both mouse and human cells. Our findings suggest a new paradigm of mTORC2 function filling an important gap in our understanding of this more mysterious mTOR-complex.
- Published
- 2019
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