Title

Non-canonical mTORC2 Signaling Regulates Brown Adipocyte Lipid Catabolism through SIRT6-FoxO1

UMMS Affiliation

Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology; Graduate School of Biomedical Sciences

Publication Date

2019-08-22

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes | Lipids | Molecular Biology

Abstract

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.

Keywords

ATGL, FoxO1, Rictor, Sirt6, UCP1, acetylation, adipocyte, brown adipose tissue, brown fat, lipid, mTOR, mTORC2, metabolism, signaling

DOI of Published Version

10.1016/j.molcel.2019.07.023

Source

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

Journal/Book/Conference Title

Molecular cell

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

31442424

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