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Talk by Anja Zeigerer

Title: "Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes"
Occasion: SFB Seminar
Host: Florian Fröhlich
Start: 01.12.2022 - 16:15
Location: CellNanOs 38/201

About the speaker: Dr. Anja Zeigerer works at the Institute for Diabetes and Cancer at the Helmholtz Centre in München.

Abstract of the talk: The class B family of G-protein coupled receptors (GPCRs) are peptide hormone receptors of the secretin family, which are connected to many human diseases, including diabetes, cancer, neurodegeneration, cardiovascular diseases and others. Although widely used as drug targets, there is little understanding about their cellular spatial temporal regulation of signaling and trafficking. Particularly interfering with glucagon receptor function in diabetes has been hampered due to its dual role in inducing glucose production, while at the same time repressing lipid synthesis, limiting its usage for pharmacotherapy. This is largely related to the gap of knowledge on glucagon receptor intracellular distribution, regulation and sights of signal transduction.

Here, we show a novel regulator of glucagon receptor trafficking, Vps37a, which influences glucagon receptor signaling by controlling its intracellular localization. VPS37A, a component of the endosomal sorting complexes required for transport 1 (ESCRT-1), is strongly reduced in the liver of diabetic and obese patients and correlates negatively with body fat in humans. Lipid-nanoparticle mediated hepatocyte specific knockdown of Vps37a caused an overactivation of glucagon receptor dependent p-Creb signaling, resulting in increased gluconeogenic gene expression and enhanced glucose production. Strikingly, the regulatory effects of Vps37a KD on glucagon signaling were restricted to glucose metabolism, as high fat diet treated mice displayed unaltered serum and liver lipid accumulations with no activation in β-oxidation. Using a new developed Cy5-labeled glucagon agonist, we show that this signaling bias is associated with an accumulation of glucagon receptor presence at early endosomes, leading to a preferential signaling to the PKA/pCreb pathway activating glucose production and gluconeogenesis without affecting lipid metabolism. Importantly, shifting the receptor back to the plasma membrane rescues the differential signaling and emphasizes the importance of the spatiotemporal localization of glucagon receptor for its metabolic effects. Altogether, these data suggest a novel function of Vps37a in glucagon receptor trafficking and signaling and highlight its thus far unknown role in regulating metabolic functions of class B GPCRs, paving the way for potential novel therapeutic interventions.