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.

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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

    • Nicolas Suárez-Zamorano
    •  & Salvatore Fabbiano

    These authors contributed equally to this work.

Affiliations

  1. University of Geneva, Faculty of Medicine, Department of Cell Physiology and Metabolism, 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. Geneva University Hospitals, Division of Radiology, Geneva, Switzerland.

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

    • Yann Seimbille
  7. University of Bern, Institute for Infectious Diseases, Bern, Switzerland.

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

    • Mirko Trajkovski

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mirko Trajkovski.

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DOI

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

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