Lipidomic analysis of adipose-derived extracellular vesicles reveals specific EV lipid sorting informative of the obesity metabolic state

The ability of exosomes to transfer cargo from donor to acceptor cells, thereby triggering phenotypic changes in the latter, has generated substantial interest in the scientific community. However, the extent to which exosomes differ from other extracellular vesicles in terms of their biogenesis and functions remains ill-defined. Here, we discuss the current knowledge on the specificities of exosomes and other types of extracellular vesicles, and their roles as important agents of cell-to-cell communication.

Intraluminal vesicles of multivesicular endosomes are either sorted for cargo degradation into lysosomes or secreted as exosomes into the extracellular milieu. The mechanisms underlying the sorting of membrane into the different populations of intraluminal vesicles are unknown. Here, we find that cargo is segregated into distinct subdomains on the endosomal membrane and that the transfer of exosome-associated domains into the lumen of the endosome did not depend on the function of the ESCRT (endosomal sorting complex required for transport) machinery, but required the sphingolipid ceramide. Purified exosomes were enriched in ceramide, and the release of exosomes was reduced after the inhibition of neutral sphingomyelinases. These results establish a pathway in intraendosomal membrane transport and exosome formation.

Adipose tissue is a major site of energy storage and plays a role in regulation of metabolism through release of adipokines. Here we show that mice with a fat-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, have major decreases in circulating exosomal miRNAs. Transplantation of white and especially brown adipose tissue (BAT) into ADicerKO mice restores circulating miRNAs associated with an improvement in glucose tolerance and a reduction of hepatic FGF21 mRNA and circulating FGF21. This gene regulation can be mimicked by administration of normal, but not AdicerKO, serum exosomes. Expression of a human-specific miRNA in BAT of one mouse in vivo can also regulate its 3’UTR-reporter in liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes a major source of circulating exosomal miRNAs, and these miRNAs can regulate gene expression in distant tissues thereby serving as novel forms of adipokines.