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

• Published in: Molecular metabolism (Germany) 2023-05, Vol.71, p.101705-101705, Article 101705
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; AKT; Animals; Brown adipose tissue; Fibroblasts - metabolism; Glucose - metabolism; Homeostasis; Insulin - metabolism; LAMTOR; Lysosome; Lysosomes - metabolism; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - metabolism; Mice; Mice, Transgenic; mTORC1/2; Nutrients; Original; Phosphatidylinositol 3-Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Ragulator; Receptor, Insulin - metabolism
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2023.101705

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. 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. 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. 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. LAMTOR complex deficiency (LT2 AKO) switches lysosomal mTORC1 “off”) causing increased AKT phosphorylation, GLUT4 and CD36 abundancy at the plasma membrane and thereby glucose and FA influx. Glucose is mainly stored in the form of glycogen, as de novo lipogenesis is not induced. Nevertheless, the mTORC1 complex is still able to inhibit IRS-1. [Display omitted]