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; D A Guertin

doi:10.1038/s41467-020-14430-w

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

Journal article

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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, …

Nature communications, v 11(1), pp 575-575

29 Jan 2020

DOI: https://doi.org/10.1038/s41467-020-14430-w

PMID: 31996678

Featured in Collection : UN Sustainable Development Goals @ Drexel

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Abstract

Acetate-CoA Ligase - metabolism

Adipocytes, Brown - metabolism

Animals

ATP Citrate (pro-S)-Lyase - metabolism

Carrier Proteins

Epigenesis, Genetic

Fatty Acid Synthases

Gene Editing

Glucose Transporter Type 4 - genetics

Glucose Transporter Type 4 - metabolism

HEK293 Cells

Histones - metabolism

Humans

Lipogenesis - genetics

Lipogenesis - physiology

Mechanistic Target of Rapamycin Complex 2 - metabolism

Mice

Mice, Inbred C57BL

PPAR gamma - metabolism

Proto-Oncogene Proteins c-akt - metabolism

Response Elements

Gene Expression

Phosphorylation

Proteomics

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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108 citations in Web of Science

110 citations in Scopus

Details

Title: mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
Creators: C Martinez Calejman - University of Massachusetts Chan Medical School
S Trefely - Drexel University
S W Entwisle - University of Washington
A Luciano - University of Massachusetts Chan Medical School
S M Jung - University of Massachusetts Chan Medical School
W Hsiao - University of Massachusetts Chan Medical School
A Torres - University of Pennsylvania
C M Hung - University of Massachusetts Chan Medical School
H Li - University of Massachusetts Chan Medical School
N W Snyder - Drexel University
J Villén - University of Washington
K E Wellen - University of Pennsylvania
D A Guertin - University of Massachusetts Chan Medical School
Publication Details: Nature communications, v 11(1), pp 575-575
Publisher: Springer Nature
Grant note: R01 AG056359 / NIA NIH HHS R35 GM119536 / NIGMS NIH HHS R01 CA196986 / NCI NIH HHS R01 GM132261 / NIGMS NIH HHS R01 DK116005 / NIDDK NIH HHS R01 DK094004 / NIDDK NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: [Retired Faculty]; A.J. Drexel Autism Institute
Web of Science ID: WOS:000563511900008
Scopus ID: 2-s2.0-85078688695
Other Identifier: 991019168512304721

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Collaboration types: Domestic collaboration
Web of Science research areas: Biochemistry & Molecular Biology

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

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Abstract

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UN Sustainable Development Goals (SDGs)

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