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

verfasst von

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

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.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

Deutsches Zentrum für Diabetesforschung e.V. (DZD)
Ludwig-Maximilians-Universität München (LMU)
Universitätsklinikum Düsseldorf
Novo Nordisk AS
Universität Leipzig
International Institute of Molecular and Cell Biology
Technische Universität München (TUM)
Universitätsklinikum Heidelberg
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

Typ

Artikel

Journal

Cell metabolism

Band

34

Seiten

1824-1842.e9

ISSN

1550-4131

Publikationsdatum

01.11.2022

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Physiologie, Molekularbiologie, Zellbiologie

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1016/j.cmet.2022.09.022 (Zugang: Offen)
https://doi.org/10.1016/j.cmet.2022.10.013 (Zugang: Offen)