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

Sekar, Revathi; Motzler, Karsten; Kwon, Yun; Novikoff, Aaron; Juelg, Julia; Najafi, Bahar; Wang, Surui; Warnke, Anna-Luisa; Seitz, Susanne; Hass, Daniela; Gancheva, Sofiya; Kahl, Sabine; Yang, Bin; Finan, Brian; Schwarz, Kathrin; Okun, Juergen G.; Roden, Michael; Blueher, Matthias; Mueller, Timo D.; Krahmer, Natalie; Behrends, Christian; Plettenburg, Oliver; Miaczynska, Marta; Herzig, Stephan und Zeigerer, Anja (2022): Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes. In: Cell Metabolism, Bd. 34, Nr. 11: S. 1824-1842

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 differ-entially 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 gluconeogen-esis without affecting b-oxidation. Shifting the receptor back to the plasma membrane rescues the differen-tial signaling and highlights the importance of the spatiotemporal localization of Gcgr for its metabolic ef-fects. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Adolf-Butenandt-Institut ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1550-4131
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 239283807
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 259130777
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 450149205