Adipose tissue is a significant source of circulating exosomal microRNAs (miRNAs), which can regulate gene expression in distant tissues. Mice with a fat-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO) and humans with lipodystrophy exhibit decreased levels of circulating exosomal miRNAs. Transplantation of white and brown adipose tissue (BAT) into ADicerKO mice restores circulating miRNAs, improves glucose tolerance, and reduces hepatic FGF21 mRNA and circulating FGF21 levels. This regulation can be mimicked by administering normal serum exosomes. Expression of a human-specific miRNA in BAT of one mouse can also regulate its 3'UTR-reporter in another mouse through serum exosomal transfer. These findings suggest that adipose-derived exosomal miRNAs serve as novel forms of adipokines, regulating gene expression in distant tissues.Adipose tissue is a significant source of circulating exosomal microRNAs (miRNAs), which can regulate gene expression in distant tissues. Mice with a fat-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO) and humans with lipodystrophy exhibit decreased levels of circulating exosomal miRNAs. Transplantation of white and brown adipose tissue (BAT) into ADicerKO mice restores circulating miRNAs, improves glucose tolerance, and reduces hepatic FGF21 mRNA and circulating FGF21 levels. This regulation can be mimicked by administering normal serum exosomes. Expression of a human-specific miRNA in BAT of one mouse can also regulate its 3'UTR-reporter in another mouse through serum exosomal transfer. These findings suggest that adipose-derived exosomal miRNAs serve as novel forms of adipokines, regulating gene expression in distant tissues.