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The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue

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The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue. / Liebscher, Gudrun; Vujic, Nemanja; Schreiber, Renate; Heine, Markus; Krebiehl, Caroline; Duta-Mare, Madalina; Lamberti, Giorgia; de Smet, Cedric H; Hess, Michael W; Eichmann, Thomas O; Hölzl, Sarah; Scheja, Ludger; Heeren, Joerg; Kratky, Dagmar; Huber, Lukas A.

in: MOL METAB, Jahrgang 71, 05.2023, S. 101705.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Liebscher, G, Vujic, N, Schreiber, R, Heine, M, Krebiehl, C, Duta-Mare, M, Lamberti, G, de Smet, CH, Hess, MW, Eichmann, TO, Hölzl, S, Scheja, L, Heeren, J, Kratky, D & Huber, LA 2023, 'The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue', MOL METAB, Jg. 71, S. 101705. https://doi.org/10.1016/j.molmet.2023.101705

APA

Liebscher, G., Vujic, N., Schreiber, R., Heine, M., Krebiehl, C., Duta-Mare, M., Lamberti, G., de Smet, C. H., Hess, M. W., Eichmann, T. O., Hölzl, S., Scheja, L., Heeren, J., Kratky, D., & Huber, L. A. (2023). The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue. MOL METAB, 71, 101705. https://doi.org/10.1016/j.molmet.2023.101705

Vancouver

Liebscher G, Vujic N, Schreiber R, Heine M, Krebiehl C, Duta-Mare M et al. The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue. MOL METAB. 2023 Mai;71:101705. https://doi.org/10.1016/j.molmet.2023.101705

Bibtex

@article{b8335719f49f473c847a6dc3bc9d30d4,
title = "The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue",
abstract = "OBJECTIVE: In brown adipose tissue (iBAT), the balance between lipid/glucose uptake and lipolysis is tightly regulated by insulin signaling. Downstream of the insulin receptor, PDK1 and mTORC2 phosphorylate AKT, which activates glucose uptake and lysosomal mTORC1 signaling. The latter requires the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator) complex, which serves to translate the nutrient status of the cell to the respective kinase. However, the role of LAMTOR in metabolically active iBAT has been elusive.METHODS: Using an AdipoqCRE-transgenic mouse line, we deleted LAMTOR2 (and thereby the entire LAMTOR complex) in adipose tissue (LT2 AKO). To examine the metabolic consequences, we performed metabolic and biochemical studies in iBAT isolated from mice housed at different temperatures (30 °C, room temperature and 5 °C), after insulin treatment, or in fasted and refed condition. For mechanistic studies, mouse embryonic fibroblasts (MEFs) lacking LAMTOR 2 were analyzed.RESULTS: Deletion of the LAMTOR complex in mouse adipocytes resulted in insulin-independent AKT hyperphosphorylation in iBAT, causing increased glucose and fatty acid uptake, which led to massively enlarged lipid droplets. As LAMTOR2 was essential for the upregulation of de novo lipogenesis, LAMTOR2 deficiency triggered exogenous glucose storage as glycogen in iBAT. These effects are cell autonomous, since AKT hyperphosphorylation was abrogated by PI3K inhibition or by deletion of the mTORC2 component Rictor in LAMTOR2-deficient MEFs.CONCLUSIONS: We identified a homeostatic circuit for the maintenance of iBAT metabolism that links the LAMTOR-mTORC1 pathway to PI3K-mTORC2-AKT signaling downstream of the insulin receptor.",
keywords = "Mice, Animals, Receptor, Insulin/metabolism, Proto-Oncogene Proteins c-akt/metabolism, Adipose Tissue, Brown/metabolism, Fibroblasts/metabolism, Mechanistic Target of Rapamycin Complex 2/metabolism, Insulin/metabolism, Mice, Transgenic, Lysosomes/metabolism, Mechanistic Target of Rapamycin Complex 1/metabolism, Nutrients, Homeostasis, Glucose/metabolism, Phosphatidylinositol 3-Kinases/metabolism, Proteins/metabolism",
author = "Gudrun Liebscher and Nemanja Vujic and Renate Schreiber and Markus Heine and Caroline Krebiehl and Madalina Duta-Mare and Giorgia Lamberti and {de Smet}, {Cedric H} and Hess, {Michael W} and Eichmann, {Thomas O} and Sarah H{\"o}lzl and Ludger Scheja and Joerg Heeren and Dagmar Kratky and Huber, {Lukas A}",
note = "Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.",
year = "2023",
month = may,
doi = "10.1016/j.molmet.2023.101705",
language = "English",
volume = "71",
pages = "101705",
journal = "MOL METAB",
issn = "2212-8778",
publisher = "Elsevier GmbH",

}

RIS

TY - JOUR

T1 - The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue

AU - Liebscher, Gudrun

AU - Vujic, Nemanja

AU - Schreiber, Renate

AU - Heine, Markus

AU - Krebiehl, Caroline

AU - Duta-Mare, Madalina

AU - Lamberti, Giorgia

AU - de Smet, Cedric H

AU - Hess, Michael W

AU - Eichmann, Thomas O

AU - Hölzl, Sarah

AU - Scheja, Ludger

AU - Heeren, Joerg

AU - Kratky, Dagmar

AU - Huber, Lukas A

N1 - Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.

PY - 2023/5

Y1 - 2023/5

N2 - OBJECTIVE: In brown adipose tissue (iBAT), the balance between lipid/glucose uptake and lipolysis is tightly regulated by insulin signaling. Downstream of the insulin receptor, PDK1 and mTORC2 phosphorylate AKT, which activates glucose uptake and lysosomal mTORC1 signaling. The latter requires the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator) complex, which serves to translate the nutrient status of the cell to the respective kinase. However, the role of LAMTOR in metabolically active iBAT has been elusive.METHODS: Using an AdipoqCRE-transgenic mouse line, we deleted LAMTOR2 (and thereby the entire LAMTOR complex) in adipose tissue (LT2 AKO). To examine the metabolic consequences, we performed metabolic and biochemical studies in iBAT isolated from mice housed at different temperatures (30 °C, room temperature and 5 °C), after insulin treatment, or in fasted and refed condition. For mechanistic studies, mouse embryonic fibroblasts (MEFs) lacking LAMTOR 2 were analyzed.RESULTS: Deletion of the LAMTOR complex in mouse adipocytes resulted in insulin-independent AKT hyperphosphorylation in iBAT, causing increased glucose and fatty acid uptake, which led to massively enlarged lipid droplets. As LAMTOR2 was essential for the upregulation of de novo lipogenesis, LAMTOR2 deficiency triggered exogenous glucose storage as glycogen in iBAT. These effects are cell autonomous, since AKT hyperphosphorylation was abrogated by PI3K inhibition or by deletion of the mTORC2 component Rictor in LAMTOR2-deficient MEFs.CONCLUSIONS: We identified a homeostatic circuit for the maintenance of iBAT metabolism that links the LAMTOR-mTORC1 pathway to PI3K-mTORC2-AKT signaling downstream of the insulin receptor.

AB - OBJECTIVE: In brown adipose tissue (iBAT), the balance between lipid/glucose uptake and lipolysis is tightly regulated by insulin signaling. Downstream of the insulin receptor, PDK1 and mTORC2 phosphorylate AKT, which activates glucose uptake and lysosomal mTORC1 signaling. The latter requires the late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator) complex, which serves to translate the nutrient status of the cell to the respective kinase. However, the role of LAMTOR in metabolically active iBAT has been elusive.METHODS: Using an AdipoqCRE-transgenic mouse line, we deleted LAMTOR2 (and thereby the entire LAMTOR complex) in adipose tissue (LT2 AKO). To examine the metabolic consequences, we performed metabolic and biochemical studies in iBAT isolated from mice housed at different temperatures (30 °C, room temperature and 5 °C), after insulin treatment, or in fasted and refed condition. For mechanistic studies, mouse embryonic fibroblasts (MEFs) lacking LAMTOR 2 were analyzed.RESULTS: Deletion of the LAMTOR complex in mouse adipocytes resulted in insulin-independent AKT hyperphosphorylation in iBAT, causing increased glucose and fatty acid uptake, which led to massively enlarged lipid droplets. As LAMTOR2 was essential for the upregulation of de novo lipogenesis, LAMTOR2 deficiency triggered exogenous glucose storage as glycogen in iBAT. These effects are cell autonomous, since AKT hyperphosphorylation was abrogated by PI3K inhibition or by deletion of the mTORC2 component Rictor in LAMTOR2-deficient MEFs.CONCLUSIONS: We identified a homeostatic circuit for the maintenance of iBAT metabolism that links the LAMTOR-mTORC1 pathway to PI3K-mTORC2-AKT signaling downstream of the insulin receptor.

KW - Mice

KW - Animals

KW - Receptor, Insulin/metabolism

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Adipose Tissue, Brown/metabolism

KW - Fibroblasts/metabolism

KW - Mechanistic Target of Rapamycin Complex 2/metabolism

KW - Insulin/metabolism

KW - Mice, Transgenic

KW - Lysosomes/metabolism

KW - Mechanistic Target of Rapamycin Complex 1/metabolism

KW - Nutrients

KW - Homeostasis

KW - Glucose/metabolism

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Proteins/metabolism

U2 - 10.1016/j.molmet.2023.101705

DO - 10.1016/j.molmet.2023.101705

M3 - SCORING: Journal article

C2 - 36907508

VL - 71

SP - 101705

JO - MOL METAB

JF - MOL METAB

SN - 2212-8778

ER -