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

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

BACKGROUND
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.

METHODS AND RESULTS
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.

CONCLUSIONS
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.