Article | Published:

Adipose-derived circulating miRNAs regulate gene expression in other tissues

Nature volume 542, pages 450455 (23 February 2017) | Download Citation

  • A Corrigendum to this article was published on 10 May 2017

Abstract

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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Acknowledgements

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).

Author information

Affiliations

  1. Section on Integrative Physiology & Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA

    • Thomas Thomou
    • , Masahiro Konishi
    • , Masaji Sakaguchi
    • , Tata Nageswara Rao
    • , Jonathon N. Winnay
    • , Ruben Garcia-Martin
    •  & C. Ronald Kahn
  2. Department of Biochemistry and Tissue Biology, University of Campinas, Campinas, Brazil

    • Marcelo A. Mori
  3. Bioinformatics Core, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, USA

    • Jonathan M. Dreyfuss
  4. Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA

    • Jonathan M. Dreyfuss
  5. ETHZ, Department of Health Sciences and Metabolism, Zurich, Switzerland

    • Christian Wolfrum
  6. Department of Biomedicine, Experimental Hematology, University Hospital Basel, Switzerland

    • Tata Nageswara Rao
  7. MGH Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    • Steven K. Grinspoon
  8. Diabetes, Endocrinology and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, Maryland, USA

    • Phillip Gorden

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Contributions

M.A.M. assisted with experimental design, generated the ADicerKO mice and designed the Ad-Luc-FGF2-3′-UTR constructs; J.M.D. carried out bioinformatics analysis; M.K. performed adenoviral injections in BAT; M.S. assisted with retro-orbital injections; C.W. created Ad-lacZ, Ad-pre-hsa-miR302f and Ad-Luc-miR302f-3′-UTR adenoviruses; T.N.R. assisted with retro-orbital and tail vain injections; J.N.W. assisted with fat depot miRNA PCR; R.G.-M. assisted with IVIS experiments and in vitro luminescence assays; S.K.G. provided human HIV lipodystrophy serum samples; P.G. provided human CGL sera samples; and T.T. and C.R.K. designed the study, collected and analysed data, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to C. Ronald Kahn.

Extended data

Supplementary information

CSV files

  1. 1.

    Supplementary Table 1

    qPCR analysis of exosomal miRNA from sera of 6 month old male ADicerKO mice vs. controls.

  2. 2.

    Supplementary Table 2

    qPCR analysis of exosomal miRNA from sera of human HIV lipodystrophy subjects vs. controls

  3. 3.

    Supplementary Table 3

    qPCR analysis of exosomal miRNA from sera of human CGL subjects vs. controls

  4. 4.

    Supplemental Table 4

    miRNA directions of change (1: increase; -1: decrease; 0: non-significant) in lipodystrophy subjects vs controls corresponding to Venn diagram in Figure 1g

  5. 5.

    Supplemental Table 5

    List of serum exosomal miRNAs that are down-regulated in both human lipodystrophies and ADicerKO mice

  6. 6.

    Supplemental Table 6

    qPCR analysis of mouse fat depots vs. controls

  7. 7.

    Supplemental Table 7

    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

  8. 8.

    Supplemental Table 8

    qPCR analysis of exosomal miRNA from serum of mouse after fat transplants (or WT) vs. saline knockout (SAL)

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DOI

https://doi.org/10.1038/nature21365

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