The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue
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 l...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-05-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782300039X |
| _version_ | 1797850511561457664 |
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| author | Gudrun Liebscher Nemanja Vujic Renate Schreiber Markus Heine Caroline Krebiehl Madalina Duta-Mare Giorgia Lamberti Cedric H. de Smet Michael W. Hess Thomas O. Eichmann Sarah Hölzl Ludger Scheja Joerg Heeren Dagmar Kratky Lukas A. Huber |
| author_facet | Gudrun Liebscher Nemanja Vujic Renate Schreiber Markus Heine Caroline Krebiehl Madalina Duta-Mare Giorgia Lamberti Cedric H. de Smet Michael W. Hess Thomas O. Eichmann Sarah Hölzl Ludger Scheja Joerg Heeren Dagmar Kratky Lukas A. Huber |
| author_sort | Gudrun Liebscher |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T19:01:18Z |
| format | Article |
| id | doaj.art-80ac827ee9ab454b8f1e8329b4b25034 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-09T19:01:18Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-80ac827ee9ab454b8f1e8329b4b250342023-04-08T05:11:03ZengElsevierMolecular Metabolism2212-87782023-05-0171101705The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissueGudrun Liebscher0Nemanja Vujic1Renate Schreiber2Markus Heine3Caroline Krebiehl4Madalina Duta-Mare5Giorgia Lamberti6Cedric H. de Smet7Michael W. Hess8Thomas O. Eichmann9Sarah Hölzl10Ludger Scheja11Joerg Heeren12Dagmar Kratky13Lukas A. Huber14Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, AustriaMolecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, AustriaInstitute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, AustriaDepartment of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, GermanyDivision of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, AustriaMolecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, AustriaDivision of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, AustriaDivision of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, AustriaInstitute of Histology and Embryology, Medical University of Innsbruck, Müllerstrasse 59, 6020 Innsbruck, AustriaInstitute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, AustriaDivision of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, AustriaDepartment of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, GermanyDepartment of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, GermanyMolecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria; BioTechMed-Graz, Mozartgasse 12, 8010 Graz, AustriaDivision of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S221287782300039XLAMTORRagulatormTORC1/2AKTBrown adipose tissueLysosome |
| spellingShingle | Gudrun Liebscher Nemanja Vujic Renate Schreiber Markus Heine Caroline Krebiehl Madalina Duta-Mare Giorgia Lamberti Cedric H. de Smet Michael W. Hess Thomas O. Eichmann Sarah Hölzl Ludger Scheja Joerg Heeren Dagmar Kratky Lukas A. Huber The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue Molecular Metabolism LAMTOR Ragulator mTORC1/2 AKT Brown adipose tissue Lysosome |
| title | The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue |
| title_full | The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue |
| title_fullStr | The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue |
| title_full_unstemmed | The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue |
| title_short | The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue |
| title_sort | lysosomal lamtor ragulator complex is essential for nutrient homeostasis in brown adipose tissue |
| topic | LAMTOR Ragulator mTORC1/2 AKT Brown adipose tissue Lysosome |
| url | http://www.sciencedirect.com/science/article/pii/S221287782300039X |
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