Adipose-Derived Circulating miRNAs Regulate Gene Expression in Other Tissues

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.