Division of Cell Biology, Biocenter, Medical University Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstr. 6, 8010 Graz, Austria.
Mol Metab. 2023 May;71:101705. doi: 10.1016/j.molmet.2023.101705. Epub 2023 Mar 11.
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.
在棕色脂肪组织（iBAT）中，脂质/葡萄糖摄取和脂肪分解之间的平衡受到胰岛素信号的严格调节。胰岛素受体下游，PDK1 和 mTORC2 磷酸化 AKT，激活葡萄糖摄取和溶酶体 mTORC1 信号。后者需要晚期内体/溶酶体衔接蛋白和 MAPK 和 mTOR 激活物（LAMTOR/Ragulator）复合物，它将细胞的营养状态转化为相应的激酶。然而，LAMTOR 在代谢活跃的 iBAT 中的作用一直难以捉摸。
使用 AdipoqCRE 转基因小鼠系，我们在脂肪组织（LT2 AKO）中敲除了 LAMTOR2（从而敲除了整个 LAMTOR 复合物）。为了研究代谢后果，我们在不同温度（30°C、室温和 5°C）、胰岛素处理后、禁食和再喂食条件下，从小鼠中分离出 iBAT 进行代谢和生化研究。为了进行机制研究，我们分析了缺乏 LAMTOR 2 的小鼠胚胎成纤维细胞（MEFs）。
在小鼠脂肪细胞中敲除 LAMTOR 复合物导致 iBAT 中胰岛素非依赖性 AKT 过度磷酸化，导致葡萄糖和脂肪酸摄取增加，从而导致脂质滴大量增大。由于 LAMTOR2 对于从头合成脂质的上调是必不可少的，因此 LAMTOR2 缺乏会触发 iBAT 中葡萄糖的外源储存为糖原。这些效应是细胞自主性的，因为 AKT 过度磷酸化被 PI3K 抑制或在 LAMTOR2 缺陷的 MEFs 中敲除 mTORC2 成分 Rictor 所消除。
我们确定了维持 iBAT 代谢的一个体内平衡回路，该回路将 LAMTOR-mTORC1 途径与胰岛素受体下游的 PI3K-mTORC2-AKT 信号联系起来。
