Abstract
Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin. In our attempt to study this pathway in adipocytes of male mice, we discover that the elimination of SMPD3 from adipocytes in vivo triggers a signal to surrounding immune cell-like preadipocytes to release EVs that carry SMPD3 mRNA. This results in a widespread increase in SMPD3 mRNA in purified null adipocytes without a change in the transcripts of other enzymes involved in ceramide metabolism. These results point to a selective mechanism by which specific mRNA molecules are acquired from the microenvironment to a level that can restore expression of mRNA and protein in a cell that is depleted of the corresponding genetic information.
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All data supporting the results of this study can be found in the article, supplementary information, and Source Data File. The sequencing data has been deposited in the GEO database under accession numbers GSE319159 (scRNAseq) and GSE319160 (RNAseq). Source data are provided with this paper.
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Acknowledgements
Funding: National Institutes of Health grants R00-DK122019, 1R01DK137791, 1R21EB035738, DRC at Washington University (NIH P30DK020579), American Heart Association (AHA 23IPA1054013) (CC). R01-DK55758, R01-DK099110, R01-DK127274, R01-DK143576, R01-DK131537, P01-AG051459, the UTSW NORC P30-DK127984 (P.E.S.). R01-DK114036, R01-DK130892, R01-DK136592 (CL). The authors thank the UT Southwestern Metabolic Phenotyping Core (RRID: SCR_026404) for its assistance with metabolic phenotyping.
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Conceptualization: C.C. and P.E.S. Investigation: C.C., C.M.G., T.O., S.C., J.B.F., M.Y.W., S.T., Y.L.P., M.R., S.A.P., Z.Y., Y.C.Z., A.L., L.G., C.K.C., and C.L. Data curation: C.C., Z.Y., C.X., and C.K.C. Formal analysis: C.C., Z.Y., C.X., A.L. Visualization: C.C., Z.Y., C.X., T.O., and P.E.S. Funding acquisition: C.C. and P.E.S. Supervision: C.C. and P.E.S. Writing-original draft: CC. Writing - review and editing C.C. and P.E.S.
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Nature Communications thanks Baisong Lu who co-reviewed with Balqees Khader; and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Crewe, C., Gliniak, C.M., Onodera, T. et al. Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71740-1
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DOI: https://doi.org/10.1038/s41467-026-71740-1
