Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue—brown especially—into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3′ UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.
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We thank M. Torriani and K. V. Fitch for assistance with HIV lipodystrophy samples; M. Lynnes, S. Kasif, and A. M. Cypess for help with reagents and discussions; and the Joslin Histology, Media and Physiology Core Facilities for help with experiments. This study was supported by grants from the NIH R01 DK082659 and R01 DK033201, the Mary K. Iacocca Professorship, and the Joslin Diabetes Center DRC Grant P30DK036836. S.K.G. was funded by grants from the NIH (P30 DK040561). M.A.M. was funded by grants from FAPESP (2010/52557-0 and 2015/01316-7).
The authors declare no competing financial interests.
Extended data figures and tables
a, Electron micrograph of exosomes isolated from ADicerKO serum by differential centrifugation. b, EXOCET ELISA assay measuring CETP protein in exosome samples, corresponding to isolated exosome number from serum of ADicerKO (KO) or Lox (WT) mice. c, qNano assay measuring the number and size of exosomes, based on tunable resistive pulse sensing technology from exosome preparations from ADicerKO (top) or Lox (bottom) mice. d, Principle component analysis of exosomal miRNA levels in ADicerKO and Lox mice, n = 4 per group. Data are mean s.e.m.
a, Heatmap showing Z scores of miRNA expression in whole serum from ADicerKO (KO) and wild-type mice (WT), and exosomal miRNAs from ADicerKO (ExoKO) or wild-type mice (ExoWT) (n = 4 per group). b, Heatmap showing Z scores of expression of exosomal miRNAs from culture supernatant of Dicerfl/fl pre-adipocytes transfected with adenovirus encoding GFP or Cre (n = 3 per group). c, Heatmap showing Z scores of miRNA expression measurements of exosomal miRNAs from the serum of 4-week-old ADicerKO (AdicerKO) and Lox (Control) mice (n = 3 per group).
a, Demographic information about human patients with HIV-associated lipodystrophy, CGL (labelled as Lipodystrophy) or control subjects. b, EXOCET ELISA assay measuring CETP protein as a measure of exosome number from isolated from human sera of individuals with HIV-associated lipodystrophy (HIV), CGL and control subjects (n = 4 per group). c, Principle component analysis of exosomal miRNA expression in patients with HIV-associated lipodystrophy or CGL, or in control subjects (n = 4 per group). Data are mean ± s.e.m.
a, Principle component analysis of miRNA expression in mouse epididymal (EPI), inguinal (ING) and BAT fat depots (n = 4 per group). b, Weight of the transplanted epididymal WAT, inguinal WAT and BAT at time of transplantation into ADicerKO mice (white bars) and at time of death (chequered bars) (n = 3). c, Weight of ADicerKO mice that underwent sham surgery (Sal) or transplantation with epididymal, inguinal, or BAT fat; Lox mice that underwent sham surgery (WT) serve as a control. Data are mean ± s.e.m.
a, Principle component analysis of serum exosomal miRNA levels in ADicerKO mice after sham surgery (Sal) or transplantation with inguinal fat (ING), epididymal fat (EPI) or BAT; Lox littermates that underwent sham surgery serve as a control (n = 4 per group). b, Circulating levels of insulin and the adipokines IL-6, leptin and adiponectin in the groups of mice in a. Two-tailed t-test, P < 0.05 (n = 3 per group).
a, Levels of Fgf21 mRNA, as assessed by qRT–PCR in liver, BAT, inguinal (ING), epididymal (Epi), pancreas (Panc), kidney (Kidn) and quadriceps muscle (Quad) tissue from ADicerKO mice (black bars) or Lox littermates (white bars). P = 0.0286 by two-tailed Mann–Whitney U test (n = 4 per group). b, Relative abundance (shown as log2 fold change (log2FC)) as assessed by qRT–PCR of miR-99a, miR-99b, and miR-100 in exosomes extracted from ADicerKO (KO) mice that underwent sham or fat-transplantation surgery (as in Fig. 2e) and wild-type mice that underwent sham surgery (n = 4 per group). Data are mean ± s.e.m. *P = 0.05.
a, Fgf21 3′ UTR luciferase-reporter activity in AML-12 mouse liver cells after transfection with 10 nM miR-99a, miR-99b, miR-100, miR-466i or control by direct electroporation. P = 0.003 by two-tailed t-test (n = 3 per group). b, Abundance of Fgf21 mRNA in AML-12 mouse liver cells following transfection with 10 nM miRNA miR-99a, miR-99b, miR-100 or miR-466i. P = 0.037, two tailed t-test (n = 3 per group). c, Hepatic Fgf21 mRNA levels by qRT–PCR followed by a 48-h incubation of AML-12 hepatic cells with exosomes derived from Lox or ADicerKO (−) mice, or with exosomes from ADicerKO mice electroporated with 10 nM miR-99a, miR-99b, miR-100 or miR-466i. P = 0.0001, two-tailed t-test (n = 3 per group). Data are mean ± s.e.m. *P = 0.05.
Extended Data Figure 8 Adipose tissue-specific miRNAs are enriched in the liver after fat transplantation.
a, qRT–PCR quantification of levels of mature miR-16, miR-201, and miR-222 in liver from Lox mice, ADicerKO mice and ADicerKO mice transplanted with BAT (KO + BAT). P = 0.02 for miR-16, P = 0.002 for miR-201, and P = 0.028 for miR-222; one-way ANOVA; significant comparisons were identified by Tukey’s multiple comparisons test (n = 3 per group). b, qRT–PCR quantification of the levels of pre-miR-16, pre-miR-201, and pre-miR-222 in the livers of Lox mice, ADicerKO mice and ADicerKO mice transplanted with BAT. P < 0.05, one-way ANOVA (n = 3 per group,). c, qRT–PCR-derived Ct values of adenoviral DNA isolated from BAT and liver tissue in Protocol 1 (BAT-p1 and Liver-p1, respectively), and from liver tissue in Protocol 2 (liver-p2), detecting adenoviral lacZ or pre-miR-302f (n = 4 per group). Data are mean ± s.e.m. *P = 0.05.
qPCR analysis of exosomal miRNA from sera of 6 month old male ADicerKO mice vs. controls. (CSV 38 kb)
qPCR analysis of exosomal miRNA from sera of human HIV lipodystrophy subjects vs. controls (CSV 32 kb)
qPCR analysis of exosomal miRNA from sera of human CGL subjects vs. controls (CSV 32 kb)
miRNA directions of change (1: increase; -1: decrease; 0: non-significant) in lipodystrophy subjects vs controls corresponding to Venn diagram in Figure 1g (CSV 5 kb)
List of serum exosomal miRNAs that are down-regulated in both human lipodystrophies and ADicerKO mice (CSV 0 kb)
qPCR analysis of mouse fat depots vs. controls (CSV 160 kb)
Logical values indicating whether transplantation of the fat depot could reconstitute the miRNA (TRUE), or not (FALSE); these values correspond to the Venn diagram in Figure 2c (CSV 5 kb)
qPCR analysis of exosomal miRNA from serum of mouse after fat transplants (or WT) vs. saline knockout (SAL) (CSV 49 kb)
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Thomou, T., Mori, M., Dreyfuss, J. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017). https://doi.org/10.1038/nature21365
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