小柯机器人

德国慕尼黑糖尿病研究中心Anja Zeigerer团队近期取得重要工作进展， 他们研究发现Vps37a通过控制胰高血糖素受体在内体的定位来调节肝脏葡萄糖的产生。这一研究成果2022年10月14日在线发表于《细胞—代谢》杂志上。

研究人员使用Cy5-胰高血糖素激动剂，发现内体蛋白Vps37a通过改变细胞内受体定位，使葡萄糖生产与Gcgr信号下游的脂质使用解耦。肝细胞特异性敲除Vps37a会导致Gcgr在内体中的积累，导致cAMP/PKA/p-Creb信号通路过度激活，从而导致葡萄糖的生成，但不影响β-氧化。将受体移回质膜挽救了差异信号，突出了Gcgr的时空定位对其代谢作用的重要性。

重要的是，Vps37a敲低的动物在高脂肪饮食喂养条件下会导致高血糖，尽管它的过度表达会降低血糖水平，这些数据揭示了内体信号传导对代谢性疾病的贡献，可用于治疗2型糖尿病。

据介绍，在哺乳动物能量平衡过程中，胰高血糖素受体（Gcgr）在调节糖和脂代谢中起着关键作用。然而，这些信号受到不同调节的机制仍然还不清楚。

附：英文原文

Title: Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes

Author: Revathi Sekar, Karsten Motzler, Yun Kwon, Aaron Novikoff, Julia Jülg, Bahar Najafi, Surui Wang, Anna-Luisa Warnke, Susanne Seitz, Daniela Hass, Sofiya Gancheva, Sabine Kahl, Bin Yang, Brian Finan, Kathrin Schwarz, Juergen G. Okun, Michael Roden, Matthias Blüher, Timo D. Müller, Natalie Krahmer, Christian Behrends, Oliver Plettenburg, Marta Miaczynska, Stephan Herzig, Anja Zeigerer

Issue&Volume: 2022-10-14

Abstract: During mammalian energy homeostasis, the glucagon receptor (Gcgr) plays a key role in regulating both glucose and lipid metabolisms. However, the mechanisms by which these distinct signaling arms are differentially regulated remain poorly understood. Using a Cy5-glucagon agonist, we show that the endosomal protein Vps37a uncouples glucose production from lipid usage downstream of Gcgr signaling by altering intracellular receptor localization. Hepatocyte-specific knockdown of Vps37a causes an accumulation of Gcgr in endosomes, resulting in overactivation of the cAMP/PKA/p-Creb signaling pathway to gluconeogenesis without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues the differential signaling and highlights the importance of the spatiotemporal localization of Gcgr for its metabolic effects. Importantly, since Vps37a knockdown in animals fed with a high-fat diet leads to hyperglycemia, although its overexpression reduces blood glucose levels, these data reveal a contribution of endosomal signaling to metabolic diseases that could be exploited for treatments of type 2 diabetes.

DOI: 10.1016/j.cmet.2022.09.022

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00412-0

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
官方网址：https://www.cell.com/cell-metabolism/home
投稿链接：https://www.editorialmanager.com/cell-metabolism/default.aspx