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

Autores
Martinez Calejman, Camila; Trefely, Sophie; Entwisle, S.W.; Luciano, Amelia; Jung, Sun Min; Hsiao, William; Torres, A.; Hung, C.M.; Li, H.; Snyder, Nathaniel W.; Villén, J.; Wellen, Kathryn E.; Guertin, D.A.
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Martinez Calejman, Camila. University of Massachusetts Medical School; Estados Unidos
Fil: Trefely, Sophie. Drexel University; Estados Unidos. University of Pennsylvania; Estados Unidos
Fil: Entwisle, S.W.. University of Washington; Estados Unidos
Fil: Luciano, Amelia. University of Massachusetts Medical School; Estados Unidos
Fil: Jung, Sun Min. University of Massachusetts Medical School; Estados Unidos
Fil: Hsiao, William. University of Massachusetts Medical School; Estados Unidos
Fil: Torres, A.. University of Pennsylvania; Estados Unidos
Fil: Hung, C.M.. University of Massachusetts Medical School; Estados Unidos
Fil: Li, H.. University of Massachusetts Medical School; Estados Unidos
Fil: Snyder, Nathaniel W.. Drexel University; Estados Unidos
Fil: Villén, J.. University of Washington; Estados Unidos
Fil: Wellen, Kathryn E.. University of Pennsylvania; Estados Unidos
Fil: Guertin, D.A.. University of Massachusetts Medical School; Estados Unidos
Materia
Brown fat
MTORC2
AKT
ACLY
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/182650
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/182650
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesisMartinez Calejman, CamilaTrefely, SophieEntwisle, S.W.Luciano, AmeliaJung, Sun MinHsiao, WilliamTorres, A.Hung, C.M.Li, H.Snyder, Nathaniel W.Villén, J.Wellen, Kathryn E.Guertin, D.A.Brown fatMTORC2AKTACLYhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3mTORC2 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.Fil: Martinez Calejman, Camila. University of Massachusetts Medical School; Estados UnidosFil: Trefely, Sophie. Drexel University; Estados Unidos. University of Pennsylvania; Estados UnidosFil: Entwisle, S.W.. University of Washington; Estados UnidosFil: Luciano, Amelia. University of Massachusetts Medical School; Estados UnidosFil: Jung, Sun Min. University of Massachusetts Medical School; Estados UnidosFil: Hsiao, William. University of Massachusetts Medical School; Estados UnidosFil: Torres, A.. University of Pennsylvania; Estados UnidosFil: Hung, C.M.. University of Massachusetts Medical School; Estados UnidosFil: Li, H.. University of Massachusetts Medical School; Estados UnidosFil: Snyder, Nathaniel W.. Drexel University; Estados UnidosFil: Villén, J.. University of Washington; Estados UnidosFil: Wellen, Kathryn E.. University of Pennsylvania; Estados UnidosFil: Guertin, D.A.. University of Massachusetts Medical School; Estados UnidosNature Publishing Group2020-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/182650Martinez Calejman, Camila; Trefely, Sophie; Entwisle, S.W.; Luciano, Amelia; Jung, Sun Min; et al.; mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis; Nature Publishing Group; Nature Communications; 11; 1; 12-2020; 1-162041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-020-14430-winfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-020-14430-winfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:45:57Zoai:ri.conicet.gov.ar:11336/182650instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:45:57.376CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
title mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
spellingShingle mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
Martinez Calejman, Camila
Brown fat
MTORC2
AKT
ACLY
title_short mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
title_full mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
title_fullStr mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
title_full_unstemmed mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
title_sort mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis
dc.creator.none.fl_str_mv Martinez Calejman, Camila
Trefely, Sophie
Entwisle, S.W.
Luciano, Amelia
Jung, Sun Min
Hsiao, William
Torres, A.
Hung, C.M.
Li, H.
Snyder, Nathaniel W.
Villén, J.
Wellen, Kathryn E.
Guertin, D.A.
author Martinez Calejman, Camila
author_facet Martinez Calejman, Camila
Trefely, Sophie
Entwisle, S.W.
Luciano, Amelia
Jung, Sun Min
Hsiao, William
Torres, A.
Hung, C.M.
Li, H.
Snyder, Nathaniel W.
Villén, J.
Wellen, Kathryn E.
Guertin, D.A.
author_role author
author2 Trefely, Sophie
Entwisle, S.W.
Luciano, Amelia
Jung, Sun Min
Hsiao, William
Torres, A.
Hung, C.M.
Li, H.
Snyder, Nathaniel W.
Villén, J.
Wellen, Kathryn E.
Guertin, D.A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Brown fat
MTORC2
AKT
ACLY
topic Brown fat
MTORC2
AKT
ACLY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Martinez Calejman, Camila. University of Massachusetts Medical School; Estados Unidos
Fil: Trefely, Sophie. Drexel University; Estados Unidos. University of Pennsylvania; Estados Unidos
Fil: Entwisle, S.W.. University of Washington; Estados Unidos
Fil: Luciano, Amelia. University of Massachusetts Medical School; Estados Unidos
Fil: Jung, Sun Min. University of Massachusetts Medical School; Estados Unidos
Fil: Hsiao, William. University of Massachusetts Medical School; Estados Unidos
Fil: Torres, A.. University of Pennsylvania; Estados Unidos
Fil: Hung, C.M.. University of Massachusetts Medical School; Estados Unidos
Fil: Li, H.. University of Massachusetts Medical School; Estados Unidos
Fil: Snyder, Nathaniel W.. Drexel University; Estados Unidos
Fil: Villén, J.. University of Washington; Estados Unidos
Fil: Wellen, Kathryn E.. University of Pennsylvania; Estados Unidos
Fil: Guertin, D.A.. University of Massachusetts Medical School; Estados Unidos
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/182650
Martinez Calejman, Camila; Trefely, Sophie; Entwisle, S.W.; Luciano, Amelia; Jung, Sun Min; et al.; mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis; Nature Publishing Group; Nature Communications; 11; 1; 12-2020; 1-16
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/182650
identifier_str_mv Martinez Calejman, Camila; Trefely, Sophie; Entwisle, S.W.; Luciano, Amelia; Jung, Sun Min; et al.; mTORC2-AKT signaling to ATP-citrate lyase drives brown adipogenesis and de novo lipogenesis; Nature Publishing Group; Nature Communications; 11; 1; 12-2020; 1-16
2041-1723
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-020-14430-w
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-020-14430-w
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846082970753957888
score 13.22299

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