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. MüllerStefanie M. Hauck, Benjamin D. Engel, Jantje M. Gerdes, Paul T. Pfluger, Natalie Krahmer, Kerstin Stemmer

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Article number709
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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