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mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis.
Nat Commun. 2020 Jan 29; 11(1):575.NC

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.

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Authors+Show Affiliations

Martinez Calejman C

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA. AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, 19104, USA.

Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA. Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, 98195, USA.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.

AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, 19104, USA.

Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA. Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, 98195, USA.

Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA. david.guertin@umassmed.edu. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA. david.guertin@umassmed.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31996678

Citation

Martinez Calejman, C, et al. "MTORC2-AKT Signaling to ATP-citrate Lyase Drives Brown Adipogenesis and De Novo Lipogenesis." Nature Communications, vol. 11, no. 1, 2020, p. 575.

Martinez Calejman C, Trefely S, Entwisle SW, et al. MTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nat Commun. 2020;11(1):575.

Martinez Calejman, C., Trefely, S., Entwisle, S. W., Luciano, A., Jung, S. M., Hsiao, W., Torres, A., Hung, C. M., Li, H., Snyder, N. W., Villén, J., Wellen, K. E., & Guertin, D. A. (2020). MTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. Nature Communications, 11(1), 575. https://doi.org/10.1038/s41467-020-14430-w

Martinez Calejman C, et al. MTORC2-AKT Signaling to ATP-citrate Lyase Drives Brown Adipogenesis and De Novo Lipogenesis. Nat Commun. 2020 Jan 29;11(1):575. PubMed PMID: 31996678.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis. AU - Martinez Calejman,C, AU - Trefely,S, AU - Entwisle,S W, AU - Luciano,A, AU - Jung,S M, AU - Hsiao,W, AU - Torres,A, AU - Hung,C M, AU - Li,H, AU - Snyder,N W, AU - Villén,J, AU - Wellen,K E, AU - Guertin,D A, Y1 - 2020/01/29/ PY - 2019/05/13/received PY - 2019/12/10/accepted PY - 2020/1/31/entrez PY - 2020/1/31/pubmed PY - 2020/2/23/medline SP - 575 EP - 575 JF - Nature communications JO - Nat Commun VL - 11 IS - 1 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/31996678/mTORC2_AKT_signaling_to_ATP_citrate_lyase_drives_brown_adipogenesis_and_de_novo_lipogenesis_ DB - PRIME DP - Unbound Medicine ER -