Adipose-derived circulating miRNAs regulate gene expression in other tissues. This study shows that mice with a fat-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO) and humans with lipodystrophy have reduced circulating exosomal miRNAs. Transplantation of white and brown adipose tissue (BAT) into ADicerKO mice restores circulating miRNAs, improving glucose tolerance and reducing hepatic FGF21 mRNA and circulating FGF21. These effects can be mimicked by administering normal serum exosomes but not those from ADicerKO mice. Expression of a human-specific miRNA in BAT can regulate its 3'UTR-reporter in liver through serum exosomal transfer, indicating that adipose tissue is a major source of circulating exosomal miRNAs that regulate gene expression in distant tissues, acting as novel adipokines. Adipose tissue is a major source of circulating exosomal miRNAs. Exosomes isolated from sera of 6-month-old ADicerKO and control mice were analyzed, revealing that ADicerKO mice had significant alterations in 422 exosomal miRNAs, with 88% reduced by more than fourfold. Many of the reduced miRNAs are highly expressed in fat, including miR-221, miR-201, miR-222, and miR-16. The loss of exosomal miRNA secretion in adipocytes lacking Dicer is cell autonomous. Transplantation of fat from normal mice into ADicerKO mice restored circulating exosomal miRNAs, indicating that adipose tissue is a major source of these miRNAs. Adipose tissue transplantation reconstitutes circulating miRNAs in lipodystrophic mice. Transplantation of fat from normal mice into ADicerKO mice restored circulating exosomal miRNAs, improving glucose tolerance and reducing insulin and FGF21 levels. BAT transplantation significantly improved glucose tolerance and reduced insulin resistance in ADicerKO mice. FGF21 is a potential target of regulation by circulating exosomal miRNAs. ADicerKO mice had a 3-fold increase in circulating FGF21, associated with increased FGF21 mRNA in liver, muscle, fat, and pancreas. BAT transplantation reduced FGF21 mRNA in liver and circulating FGF21 levels. miR-99b was identified as a candidate miRNA that targets the 3'-UTR of murine FGF21 mRNA. Exosomes from ADicerKO mice had no effect on FGF21-3'UTR luciferase activity, but exosomes reconstituted with miR-99b reduced this activity, indicating that miR-99b regulates FGF21 expression in liver. Regulation of liver gene expression by adipose-produced circulating exosomal miRNAs. Adipose-derived circulating miRNAsAdipose-derived circulating miRNAs regulate gene expression in other tissues. This study shows that mice with a fat-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO) and humans with lipodystrophy have reduced circulating exosomal miRNAs. Transplantation of white and brown adipose tissue (BAT) into ADicerKO mice restores circulating miRNAs, improving glucose tolerance and reducing hepatic FGF21 mRNA and circulating FGF21. These effects can be mimicked by administering normal serum exosomes but not those from ADicerKO mice. Expression of a human-specific miRNA in BAT can regulate its 3'UTR-reporter in liver through serum exosomal transfer, indicating that adipose tissue is a major source of circulating exosomal miRNAs that regulate gene expression in distant tissues, acting as novel adipokines. Adipose tissue is a major source of circulating exosomal miRNAs. Exosomes isolated from sera of 6-month-old ADicerKO and control mice were analyzed, revealing that ADicerKO mice had significant alterations in 422 exosomal miRNAs, with 88% reduced by more than fourfold. Many of the reduced miRNAs are highly expressed in fat, including miR-221, miR-201, miR-222, and miR-16. The loss of exosomal miRNA secretion in adipocytes lacking Dicer is cell autonomous. Transplantation of fat from normal mice into ADicerKO mice restored circulating exosomal miRNAs, indicating that adipose tissue is a major source of these miRNAs. Adipose tissue transplantation reconstitutes circulating miRNAs in lipodystrophic mice. Transplantation of fat from normal mice into ADicerKO mice restored circulating exosomal miRNAs, improving glucose tolerance and reducing insulin and FGF21 levels. BAT transplantation significantly improved glucose tolerance and reduced insulin resistance in ADicerKO mice. FGF21 is a potential target of regulation by circulating exosomal miRNAs. ADicerKO mice had a 3-fold increase in circulating FGF21, associated with increased FGF21 mRNA in liver, muscle, fat, and pancreas. BAT transplantation reduced FGF21 mRNA in liver and circulating FGF21 levels. miR-99b was identified as a candidate miRNA that targets the 3'-UTR of murine FGF21 mRNA. Exosomes from ADicerKO mice had no effect on FGF21-3'UTR luciferase activity, but exosomes reconstituted with miR-99b reduced this activity, indicating that miR-99b regulates FGF21 expression in liver. Regulation of liver gene expression by adipose-produced circulating exosomal miRNAs. Adipose-derived circulating miRNAs