mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis

C. Martinez Calejman, S. Trefely, S. W. Entwisle, A. Luciano, S. M. Jung, W. Hsiao, A. Torres, C. M. Hung, H. Li, N. W. Snyder, J. Villén, K. E. Wellen and D. A. Guertin ()
Additional contact information
C. Martinez Calejman: University of Massachusetts Medical School
S. Trefely: University of Pennsylvania
S. W. Entwisle: University of Washington
A. Luciano: University of Massachusetts Medical School
S. M. Jung: University of Massachusetts Medical School
W. Hsiao: University of Massachusetts Medical School
A. Torres: University of Pennsylvania
C. M. Hung: University of Massachusetts Medical School
H. Li: University of Massachusetts Medical School
N. W. Snyder: Drexel University
J. Villén: University of Washington
K. E. Wellen: University of Pennsylvania
D. A. Guertin: University of Massachusetts Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.

Date: 2020
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DOI: 10.1038/s41467-020-14430-w

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