Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Microbiota depletion promotes browning of white adipose tissue and reduces obesity

Nature Medicine volume 21, pages 1497–1501 (2015)Cite this article

Subjects

Abstract

Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity1. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning2,3,4. Here we show that the development of functional beige fat in the inguinal subcutaneous adipose tissue (ingSAT) and perigonadal visceral adipose tissue (pgVAT) is promoted by the depletion of microbiota either by means of antibiotic treatment or in germ-free mice. This leads to improved glucose tolerance and insulin sensitivity and decreased white fat and adipocyte size in lean mice, obese leptin-deficient ( ob/ob ) mice and high-fat diet (HFD)-fed mice. Such metabolic improvements are mediated by eosinophil infiltration, enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by the suppression of type 2 cytokine signaling, and they are reversed by recolonization of the antibiotic-treated or germ-free mice with microbes. These results provide insight into the microbiota-fat signaling axis and beige-fat development in health and metabolic disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Microbiota depletion directs glucose uptake primarily to the white adipose tissue (WAT) and improves sensitivity to insulin.
Figure 2: Microbiota depletion promotes browning of ingSAT and pgVAT.
Figure 3: Microbiota depletion promotes browning in thermoneutral and obese animals and improves metabolic disease.
Figure 4: Browning of ingSAT after microbiota depletion is mediated by type 2 cytokine signaling.

Similar content being viewed by others

References

  1. Stanford, K.I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).

    Article  CAS  Google Scholar 

  2. Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).

    Article  CAS  Google Scholar 

  3. Wu, J., Cohen, P. & Spiegelman, B. M. Adaptive thermogenesis in adipocytes: Is beige the new brown? Genes Dev. 27, 234–250 (2013).

    Article  CAS  Google Scholar 

  4. Peirce, V., Carobbio, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76–83 (2014).

    Article  CAS  Google Scholar 

  5. Koren, O. et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150, 470–480 (2012).

    Article  CAS  Google Scholar 

  6. Ridaura, V.K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).

    Article  Google Scholar 

  7. Liou, A. P. et al. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci. Transl. Med. 5, 178ra141 (2013).

    Article  Google Scholar 

  8. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    Article  CAS  Google Scholar 

  9. Cox, L.M. & Blaser, M.J. Antibiotics in early life and obesity. Nat. Rev. Endocrinol. 11, 182–190 (2015).

    Article  Google Scholar 

  10. Chou, C.J., Membrez, M. & Blancher, F. Gut decontamination with norfloxacin and ampicillin enhances insulin sensitivity in mice. Nestle Nutr. Workshop Ser. Pediatr. Program. 62, 127–137 discussion 137–140 (2008).

    Article  CAS  Google Scholar 

  11. Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. USA 101, 15718–15723 (2004).

    Article  Google Scholar 

  12. Hwang, I. et al. Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity. FASEB J. 29, 2397–2411 (2015).

    Article  CAS  Google Scholar 

  13. El Kaoutari, A., Armougom, F., Gordon, J.I., Raoult, D. & Henrissat, B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nat. Rev. Microbiol. 11, 497–504 (2013).

    Article  CAS  Google Scholar 

  14. Feldmann, H.M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203–209 (2009).

    Article  CAS  Google Scholar 

  15. Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu. Rev. Immunol. 32, 609–634 (2014).

    Article  CAS  Google Scholar 

  16. Lee, M.W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015).

    Article  CAS  Google Scholar 

  17. Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).

    Article  CAS  Google Scholar 

  18. Martinez, F.O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009).

    Article  CAS  Google Scholar 

  19. Nguyen, K.D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).

    Article  CAS  Google Scholar 

  20. Molofsky, A.B. et al. Interleukin-33 and interferon-γ counter-regulate group 2 innate lymphoid cell activation during immune perturbation. Immunity 43, 161–174 (2015).

    Article  CAS  Google Scholar 

  21. Grivennikov, S.I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).

    Article  CAS  Google Scholar 

  22. Sun, L. & Trajkovski, M. MiR-27 orchestrates the transcriptional regulation of brown adipogenesis. Metabolism 63, 272–282 (2014).

    Article  CAS  Google Scholar 

  23. Trajkovski, M., Ahmed, K., Esau, C.C. & Stoffel, M. MyomiR-133 regulates brown fat differentiation through Prdm16. Nat. Cell Biol. 14, 1330–1335 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Gustafsson Trajkovska, C. Wollheim and R. Coppari for their discussions and critical reading of the manuscript; C. Darimont for help with bomb calorimetric measurements; P. Maechler and M. Karaca for help with and discussions about the OCR measurements; S. Startchik for help with image quantifications; ERC-2013-StG-281904 to S.H. for partial funding of the gnotobiotic research; and G. Waksman for support. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement no. 336607 (ERC-2013-StG-336607); the Louis-Jeantet Foundation; Fondation pour Recherches Médicales; Novartis Foundation (14B053) and the Swiss National Science Foundation (SNSF) Professorship (PP00P3_144886) to M.T.

Author information

Author notes

  1. Nicolas Suárez-Zamorano and Salvatore Fabbiano: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Physiology and Metabolism, University of Geneva, Faculty of Medicine, Centre Médical Universitaire (CMU), Geneva, Switzerland

    Nicolas Suárez-Zamorano, Salvatore Fabbiano, Claire Chevalier, Ozren Stojanović, Ana Stevanović, Christelle Veyrat-Durebex, Valentina Tarallo, Dorothée Rigo & Mirko Trajkovski

  2. University of Geneva, Diabetes Centre, Faculty of Medicine, Geneva, Switzerland

    Nicolas Suárez-Zamorano, Salvatore Fabbiano, Claire Chevalier, Ozren Stojanović, Ana Stevanović, Christelle Veyrat-Durebex, Valentina Tarallo, Dorothée Rigo & Mirko Trajkovski

  3. Geneva University Hospitals, Centre for BioMedical Imaging (CIBM), Geneva, Switzerland

    Didier J Colin & Stéphane Germain

  4. Alkaloid AD Skopje, Skopje, Republic of Macedonia

    Miroslava Ilievska

  5. Division of Radiology, Geneva University Hospitals, Geneva, Switzerland

    Xavier Montet

  6. Division of Nuclear Medicine, Geneva University Hospitals, Cyclotron Unit, Geneva, Switzerland

    Yann Seimbille

  7. University of Bern, Institute for Infectious Diseases, Bern, Switzerland

    Siegfried Hapfelmeier

  8. Division of Biosciences, University College London (UCL), Institute of Structural and Molecular Biology, London, UK

    Mirko Trajkovski

Authors
  1. Nicolas Suárez-Zamorano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salvatore Fabbiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claire Chevalier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ozren Stojanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Didier J Colin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ana Stevanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christelle Veyrat-Durebex
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Valentina Tarallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dorothée Rigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stéphane Germain
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Miroslava Ilievska
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xavier Montet
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yann Seimbille
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Siegfried Hapfelmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mirko Trajkovski
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.S.-Z. and S.F. designed and performed experiments, analyzed data and prepared figures; C.C., O.S., C.V.-D. and A.S. performed experiments and analyzed data; D.J.C., S.G., X.M. and Y.S. did the PET-CT and the CT experiments; V.T. and D.R. participated in experiments, and D.R. gave technical support; S.H. and M.I. provided germ-free mice and antibiotics, respectively, and advised on their use; M.T. designed the work, participated in experiments, analyzed data, prepared the figures and wrote the manuscript with input from all co-authors.

Corresponding author

Correspondence to Mirko Trajkovski.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 9743 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suárez-Zamorano, N., Fabbiano, S., Chevalier, C. et al. Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat Med 21, 1497–1501 (2015). https://doi.org/10.1038/nm.3994

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3994

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research