Details
| Original language | English |
|---|---|
| Pages (from-to) | 1824-1842.e9 |
| Journal | Cell metabolism |
| Volume | 34 |
| Issue number | 11 |
| Early online date | 14 Oct 2022 |
| Publication status | Published - 1 Nov 2022 |
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.
Keywords
- diabetes, endosomal trafficking and signaling, ESCRTs, glucagon receptor biology and signaling, liver metabolism
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physiology
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology
Sustainable Development Goals
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In: Cell metabolism, Vol. 34, No. 11, 01.11.2022, p. 1824-1842.e9.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes
AU - Sekar, Revathi
AU - Motzler, Karsten
AU - Kwon, Yun
AU - Novikoff, Aaron
AU - Jülg, Julia
AU - Najafi, Bahar
AU - Wang, Surui
AU - Warnke, Anna Luisa
AU - Seitz, Susanne
AU - Hass, Daniela
AU - Gancheva, Sofiya
AU - Kahl, Sabine
AU - Yang, Bin
AU - Finan, Brian
AU - Schwarz, Kathrin
AU - Okun, Juergen G.
AU - Roden, Michael
AU - Blüher, Matthias
AU - Müller, Timo D.
AU - Krahmer, Natalie
AU - Behrends, Christian
AU - Plettenburg, Oliver
AU - Miaczynska, Marta
AU - Herzig, Stephan
AU - Zeigerer, Anja
N1 - Funding Information: We acknowledge J. Trejo, D. Drucker, Ü. Coskun, and A. Messias for helpful discussions. We thank J. Biebl and Q. Reinold for mouse work, the pathology core facility for H&E stainings, and I. Patten for editorial support. L. Harrison created the graphical abstract in Biorender. This work was financially supported by the German Research Foundation (DFG) grant ZE1037/1-3, EFSD grant 01KU1501C, BMBF grant 16LW0116k, and Marie Sklodowska-Curie ITN, EU Horizon 2020 (EndoConnect) to A.Z.; DFG-TRR152, DFG-TRR296, DFG-SFB1123, GRK2816, DZD, and the ERC-coG Trusted 101044445 to T.D.M.; DFG-CRC/TRR333 and AMPro funding from the Helmholtz Association to S.H. N.K. is funded by Emmy-Noether DFG (KR5166/1-1). C.B. was supported by the DFG within the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and the CRC 1177 (ID 259130777). A.Z. designed and directed the project and R.S. designed the experiments. R.S. and K.M. performed experiments. K.M. developed the overexpression construct. Y.K. performed western blots and image analysis. A.N. and T.D.M. designed Gαs experiments, and T.D.M. provided Gcgr KO mice. J.J. and C.B. performed protein purification and pull-down experiments. B.N. S.W. and D.H. helped with western blots and animal experiments. A.-L.W. and O.P. designed and synthesized Cy5-glucagon. S.S. performed qPCRs. S.G. S.K. M.R. and M.B. provided patient samples and performed correlation analysis. B.Y. and B.F. synthesized IUB396. K.S. and J.G.O. measured serum amino acids. N.K. M.M. and S.H. helped in experimental design. A.Z. and R.S. wrote the manuscript. B.F. and B.Y. are employees of Novo Nordisk.
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.
AB - 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.
KW - diabetes
KW - endosomal trafficking and signaling
KW - ESCRTs
KW - glucagon receptor biology and signaling
KW - liver metabolism
UR - http://www.scopus.com/inward/record.url?scp=85140805138&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2022.09.022
DO - 10.1016/j.cmet.2022.09.022
M3 - Article
C2 - 36243006
AN - SCOPUS:85140805138
VL - 34
SP - 1824-1842.e9
JO - Cell metabolism
JF - Cell metabolism
SN - 1550-4131
IS - 11
ER -