2. Academic Validation
  3. The lysosomal LAMTOR / Ragulator complex is essential for nutrient homeostasis in brown adipose tissue

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

  • Mol Metab. 2023 Mar 10;101705. doi: 10.1016/j.molmet.2023.101705.
Gudrun Liebscher 1,  Nemanja Vujic 2,  Renate Schreiber 3,  Markus Heine 4,  Caroline Krebiehl 1,  Madalina Duta-Mare 2,  Giorgia Lamberti 1,  Cedric H de Smet 1,  Michael W Hess 5,  Thomas O Eichmann 3,  Sarah Hölzl 1,  Ludger Scheja 4,  Joerg Heeren 4,  Dagmar Kratky 6,  Lukas A Huber 7
Affiliations

Affiliations

  • 1 Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
  • 2 Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria.
  • 3 Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
  • 4 Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
  • 5 Institute of Histology and Embryology, Medical University of Innsbruck, Müllerstrasse 59, 6020 Innsbruck, Austria.
  • 6 Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria; BioTechMed-Graz, Mozartgasse 12, 8010 Graz, Austria.
  • 7 Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: [email protected].
PMID: 36907508 DOI: 10.1016/j.molmet.2023.101705
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

AKT; LAMTOR; Ragulator; brown adipose tissue; lysosome; mTORC1/2.

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