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

authored by

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.

Organisation(s)

Institute of Organic Chemistry

External Organisation(s)

German Center for Diabetes Research (DZD)
Ludwig-Maximilians-Universität München (LMU)
University Hospital Düsseldorf
Novo Nordisk AS
Leipzig University
International Institute of Molecular and Cell Biology
Technical University of Munich (TUM)
Universitätsklinikum Heidelberg
Helmholtz Zentrum München - German Research Center for Environmental Health

Type

Article

Journal

Cell metabolism

Volume

34

Pages

1824-1842.e9

ISSN

1550-4131

Publication date

01.11.2022

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Physiology, Molecular Biology, Cell Biology

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1016/j.cmet.2022.09.022 (Access: Open)
https://doi.org/10.1016/j.cmet.2022.10.013 (Access: Open)