Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1
Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes | Lipids | Molecular Biology
mTORC2 controls glucose and lipid metabolism, but the mechanisms are 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 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.
ATGL, FoxO1, Rictor, Sirt6, UCP1, acetylation, adipocyte, brown adipose tissue, brown fat, lipid, mTOR, mTORC2, metabolism, signaling
DOI of Published Version
Mol Cell. 2019 Aug 22;75(4):807-822.e8. doi: 10.1016/j.molcel.2019.07.023. Link to article on publisher's site
Jung SM, Hung C, Hildebrand SR, Sanchez-Gurmaches J, Mukhopadhyay D, Calejman CM, Luciano AK, Hsiao W, Tang Y, Li H, Guertin DA. (2019). Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1. Program in Molecular Medicine Publications and Presentations. https://doi.org/10.1016/j.molcel.2019.07.023. Retrieved from https://escholarship.umassmed.edu/pmm_pp/130