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

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 en...

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Main Authors: Sekar, Revathi (Author) , Motzler, Karsten (Author) , Kwon, Yun (Author) , Novikoff, Aaron (Author) , Jülg, Julia (Author) , Najafi, Bahar (Author) , Wang, Surui (Author) , Warnke, Anna-Luisa (Author) , Seitz, Susanne (Author) , Hass, Daniela (Author) , Gancheva, Sofiya (Author) , Kahl, Sabine (Author) , Yang, Bin (Author) , Finan, Brian (Author) , Schwarz, Kathrin (Author) , Okun, Jürgen G. (Author) , Roden, Michael (Author) , Blüher, Matthias (Author) , Müller, Timo D. (Author) , Krahmer, Natalie (Author) , Behrends, Christian (Author) , Plettenburg, Oliver (Author) , Miaczynska, Marta (Author) , Herzig, Stephan (Author) , Zeigerer, Anja (Author)
Format: Article (Journal)
Language:English
Published: 14 October 2022
In: Cell metabolism
Year: 2022, Volume: 34, Issue: 11, Pages: 1824-1842, e1-e9
ISSN:1932-7420
DOI:10.1016/j.cmet.2022.09.022
Online Access:Verlag, Volltext: https://doi.org/10.1016/j.cmet.2022.09.022
Verlag, Volltext: https://www.sciencedirect.com/science/article/pii/S1550413122004120
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Author Notes: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, and Anja Zeigerer
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Summary: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.
Item Description:Dateiversion vom: 1. November 2022
Gesehen am 18.01.2023
Physical Description:Online Resource
ISSN:1932-7420
DOI:10.1016/j.cmet.2022.09.022

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