Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo

Konxhe Kulaj, Alexandra Harger, Michaela Bauer, Özüm S. Caliskan, Tilak Kumar Gupta, Dapi Menglin Chiang, Edward Milbank, Josefine Reber, Angelos Karlas, Petra Kotzbeck, David N. Sailer, Francesco Volta, Dominik Lutter, Sneha Prakash, Juliane Merl-Pham, Vasilis Ntziachristos, Hans Hauner, Michael W. Pfaffl, Matthias H. Tschöp, Timo D. Müller, Stefanie M. Hauck, Benjamin D. Engel, Jantje M. Gerdes, Paul T. Pfluger, Natalie Krahmer and Kerstin Stemmer ()
Additional contact information
Konxhe Kulaj: Helmholtz Zentrum München
Alexandra Harger: Helmholtz Zentrum München
Michaela Bauer: Helmholtz Zentrum München
Özüm S. Caliskan: Helmholtz Zentrum München
Tilak Kumar Gupta: Max Planck Institute of Biochemistry
Dapi Menglin Chiang: Technical University of Munich
Edward Milbank: Helmholtz Zentrum München
Josefine Reber: Helmholtz Zentrum München
Angelos Karlas: Helmholtz Zentrum München
Petra Kotzbeck: Helmholtz Zentrum München
David N. Sailer: Helmholtz Zentrum München
Francesco Volta: Helmholtz Zentrum München
Dominik Lutter: Helmholtz Zentrum München
Sneha Prakash: Helmholtz Zentrum München
Juliane Merl-Pham: Helmholtz Zentrum München
Vasilis Ntziachristos: Helmholtz Zentrum München
Hans Hauner: Technical University of Munich
Michael W. Pfaffl: Technical University of Munich
Matthias H. Tschöp: Helmholtz Zentrum München
Timo D. Müller: Helmholtz Zentrum München
Stefanie M. Hauck: Helmholtz Zentrum München
Benjamin D. Engel: Helmholtz Zentrum München
Jantje M. Gerdes: Helmholtz Zentrum München
Paul T. Pfluger: Helmholtz Zentrum München
Natalie Krahmer: Helmholtz Zentrum München
Kerstin Stemmer: Helmholtz Zentrum München

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand.

Date: 2023
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DOI: 10.1038/s41467-023-36148-1

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