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

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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.

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.

Author information

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.

Correspondence to Natasa Petrovic.

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