EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events

Neuhaus, M. et al. (2023) EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events. Molecular Biology of the Cell, 34(12), ar124. (doi: 10.1091/mbc.e23-03-0078) (PMID:37703099) (PMCID:PMC10846623)

Abstract

Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.

• Item Type: Articles
• Additional Information: This work was financially supported by the Swedish Research Council (2019-00978) and Strategic Research Area Exodiab (2009-1039), the Swedish Foundation for Strategic Research (IRC15-0067), Novo Nordisk (NNF20OC0063659), Swedish Diabetes Foundation, The Crafoord Foundation, and Albert Påhlsson Foundation. Holly Taylor was supported by a Diabetes UK PhD studentship (18/0005905 to G.W.G. and N.J.B.) and Diabetes UK grants (18/0005847 and 15/0005246 to G.W.G. and N.J.B.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bremner-Hart, Dr Shaun
• Authors: Neuhaus, M., Fryklund, C., Taylor, H., Borreguero-Muñoz, A., Kopietz, F., Ardalani, H., Rogova, O., Stirrat, L., Bremner, S. K., Spégel, P., Bryant, N. J., Gould, G. W., and Stenkula, K. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Molecular Biology of the Cell
• Publisher: American Society for Cell Biology
• ISSN: 1939-4586
• ISSN (Online): 1939-4586
• Copyright Holders: Copyright: © 2023 Neuhaus et al.
• First Published: First published in Molecular Biology of the Cell 34(12): ar124
• Publisher Policy: Reproduced under a Creative Commons licence

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
304626		Insulin receptor phosphorylation of SNARE proteins at the plasma membrane?	Gwyn Gould	Diabetes UK (DIABETUK)	18/0005905	School of Molecular Biosciences
173377		How does Cholesterol regulate insulin action in adipocytes?	Gwyn Gould	Diabetes UK (DIABETUK)	15/0005246	SMB - Molecular Biosciences