Adipose-derived circulating miRNAs regulate gene expression in other tissues

  • Nature volume 542, pages 450455 (23 February 2017)
  • doi:10.1038/nature21365
  • Download Citation


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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  1. 1.

    , & The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597–610 (2010)

  2. 2.

    et al. Mir193b-365 is essential for brown fat differentiation. Nat. Cell Biol. 13, 958–965 (2011)

  3. 3.

    et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011)

  4. 4.

    MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009)

  5. 5.

    & Diversifying microRNA sequence and function. Nat. Rev. Mol. Cell Biol. 14, 475–488 (2013)

  6. 6.

    et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011)

  7. 7.

    , , & Curr Protoc Cell Biol Chapter 3, Unit 3 22 (2006)

  8. 8.

    et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell. Mol. Life Sci. 68, 2667–2688 (2011)

  9. 9.

    & Dysregulation of microRNA biogenesis and gene silencing in cancer. Sci. Signal. 8, re3 (2015)

  10. 10.

    , & MicroRNAs and metabolism crosstalk in energy homeostasis. Cell Metab. 18, 312–324 (2013)

  11. 11.

    et al. Adipose tissue microRNAs as regulators of CCL2 production in human obesity. Diabetes 61, 1986–1993 (2012)

  12. 12.

    et al. miRNA and protein expression profiles of visceral adipose tissue reveal miR-141/YWHAG and miR-520e/RAB11A as two potential miRNA/protein target pairs associated with severe obesity. J. Proteome Res. 11, 3358–3369 (2012)

  13. 13.

    , , & Potential therapeutic role of microRNAs in ischemic heart disease. J. Cardiol. 61, 315–320 (2013)

  14. 14.

    , , , & Diabetes mellitus, a microRNA-related disease? Transl. Res. 157, 253–264 (2011)

  15. 15.

    et al. Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab. 16, 336–347 (2012)

  16. 16.

    et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J. Clin. Invest. 124, 3339–3351 (2014)

  17. 17.

    et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008)

  18. 18.

    , & Exosome isolation for proteomic analyses and RNA profiling. Methods Mol. Biol. 728, 235–246 (2011)

  19. 19.

    et al. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J. Biol. Chem. 273, 20121–20127 (1998)

  20. 20.

    & Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr. Opin. Cell Biol. 16, 415–421 (2004)

  21. 21.

    et al. MiRNA expression profile of human subcutaneous adipose and during adipocyte differentiation. PLoS One 5, e9022 (2010)

  22. 22.

    et al. Decreased microRNA-221 is associated with high levels of TNF-α in human adipose tissue-derived mesenchymal stem cells from obese woman. Cell. Physiol. Biochem. 32, 127–137 (2013)

  23. 23.

    et al. Cell-specific dysregulation of microRNA expression in obese white adipose tissue. J. Clin. Endocrinol. Metab. 99, 2821–2833 (2014)

  24. 24.

    et al. Gene-chip studies of adipogenesis-regulated microRNAs in mouse primary adipocytes and human obesity. BMC Endocr. Disord. 11, 7 (2011)

  25. 25.

    & microRNAs in the regulation of adipogenesis and obesity. Curr. Mol. Med. 11, 304–316 (2011)

  26. 26.

    , & Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 26, 312–324 (2012)

  27. 27.

    et al. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437 (2007)

  28. 28.

    & miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 43, D146–D152 (2015)

  29. 29.

    et al. MicroRNA profiling of human gastric cancer. Mol. Med. Rep. 2, 963–970 (2009)

  30. 30.

    et al. Gene delivery to adipose tissue using transcriptionally targeted rAAV8 vectors. PLoS One 9, e116288 (2014)

  31. 31.

    et al. Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J. Neurooncol. 115, 343–351 (2013)

  32. 32.

    , , & Tumor-exosomes and leukocyte activation: an ambivalent crosstalk. Cell Commun. Signal. 10, 37 (2012)

  33. 33.

    et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007)

  34. 34.

    Adipokines - removing road blocks to obesity and diabetes therapy. Mol. Metab. 3, 230–240 (2014)

  35. 35.

    , & Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9, 581–593 (2009)

  36. 36.

    et al. Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J. Clin. Invest. 124, 2136–2146 (2014)

  37. 37.

    et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat. Cell Biol. 14, 249–256 (2012)

  38. 38.

    et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2, 282 (2011)

  39. 39.

    et al. Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood 121, 984–995 (2013)

  40. 40.

    et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2, ra81 (2009)

  41. 41.

    et al. Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. Neuro-oncol. 18, 58–69 (2016)

  42. 42.

    et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One 4, e4722 (2009)

  43. 43.

    , , & The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One 7, e30679 (2012)

  44. 44.

    , , & Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39, 7223–7233 (2011)

  45. 45.

    et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 35, 2383–2390 (2014)

  46. 46.

    , , & ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 40, D1241–D1244 (2012)

  47. 47.

    et al. A novel and universal method for microRNA RT–qPCR data normalization. Genome Biol. 10, R64 (2009)

  48. 48.

    Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article3 (2004)

  49. 49.

    , , & Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

  50. 50.

    , , & Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7, 410–420 (2008)

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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).

Author information


  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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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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