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Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice

Nature Metabolism volume 1, pages 830–843 (2019)Cite this article

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Matters Arising to this article was published on 13 April 2020

An Author Correction to this article was published on 10 September 2019

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Abstract

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of ‘physiologically humanized’ mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.

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Fig. 1: iBAT in physiologically humanized mice morphologically phenocopies human supraclavicular BAT.
Fig. 2: iBAT in physiologically humanized mice retains a distinct ‘thermogenic’ molecular signature.
Fig. 3: Under humanized conditions, the distinguishing power of the suggested brown versus brite/beige marker genes is diminished.
Fig. 4: Physiological humanization leads to more extensive transcriptome alterations in iBAT than in ingWAT.
Fig. 5: iBAT in physiologically humanized mice molecularly phenocopies human supraclavicular BAT.
Fig. 6: Browning probability in human and mouse adipose tissues.
Fig. 7: Physiologically humanized mouse iBAT, but not ingWAT, retains high browning capacity.

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Data availability

The RNA-Seq data of human samples have been deposited with the European Nucleotide Archive with the accession number PRJEB20634(ref. 36). The RNA-Seq data of mouse samples have been deposited with Array Express with accession nos. E-MTAB-7561 (iBAT and ingWAT samples from standard and physiologically humanized mice) and E-MTAB-7565 (iBAT and ingWAT samples from cold-acclimated mice).

Code availability

The detailed MATLAB code for the PCA can be obtained upon reasonable request.

Change history

  • 10 September 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

The authors acknowledge support from the Swedish Research Council (VR-2017-01379 and VR-2017-04715), Knut and Alice Wallenberg Foundation (WA2015-0009), the Novo Nordisk Foundation (NNF17C0027058), Magnus Bergvalls Stiftelse (2017-02199 and 2018-02969), Diabetesfonden (DIA 2018-381) and European Union Collaborative projects ADAPT (EU201100) and DIABAT (EU278373). The authors thank the Experimental Core Facility staff for breeding the mice and the Imaging Facility at Stockholm University for the help with confocal microscopy. The authors also thank A. Smialowska and O. Dethlefsen for valuable advice regarding the bioinformatics analyses and M. Jastroch and F. Perocchi for their help with interpreting the browning probability results obtained with the PROFAT online tool.

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Author notes

  1. Jasper M. A. de Jong

    Present address: Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA

  2. Alexander W. Fischer

    Present address: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA

  3. Alexander W. Fischer

    Present address: Department of Cell Biology, Harvard Medical School, Boston, MA, USA

Authors and Affiliations

  1. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden

    Jasper M. A. de Jong, Alexander W. Fischer, Muhammad Hamza Bokhari, Barbara Cannon, Jan Nedergaard & Natasa Petrovic

  2. Institute of Food, Nutrition and Health, Eidgenössische Technische Hochschule Zürich, Schwerzenbach, Switzerland

    Wenfei Sun, Nuno D. Pires, Miroslav Balaz & Christian Wolfrum

  3. Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy

    Andrea Frontini

  4. The Centre of Inflammation and Metabolism and Centre for Physical Activity Research Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark

    Naja Z. Jespersen, Søren Nielsen & Camilla Scheele

  5. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Naja Z. Jespersen & Camilla Scheele

  6. Novo Nordisk Research Centre Oxford, Oxford, UK

    Amir Feizi

  7. Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden

    Katarina Petrovic

  8. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Alexander W. Fischer

  9. Department of Surgery, Turku University Hospital, Turku, Finland

    Tarja Niemi

  10. Turku PET Centre, University of Turku, Turku, Finland

    Pirjo Nuutila & Kirsi Virtanen

  11. Department of Experimental and Clinical Medicine, University of Ancona, Ancona, Italy

    Saverio Cinti

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Contributions

J.J., J.N., C.W. and N.P. designed the research. J.J., W.S., A.Frontini, A.W.F. and N.P. performed the experiments. J.J., W.S., N.D.P., M.B., K.P., A.Feizi, M.H.B. and N.P. performed the bioinformatics analyses. A.Frontini, T.N., P.N., S.C., K.V., N.Z.J., S.N., C.S. and C.W. provided essential materials and made comments on the manuscript. J.J., B.C., J.N. and N.P. wrote the manuscript. N.P. supervised the research.

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Correspondence to Natasa Petrovic.

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de Jong, J.M.A., Sun, W., Pires, N.D. et al. Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nat Metab 1, 830–843 (2019). https://doi.org/10.1038/s42255-019-0101-4

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