Genetic and functional characterization of clonally derived adult human brown adipocytes (original) (raw)

Nature Medicine volume 21, pages 389–394 (2015)Cite this article

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Abstract

Brown adipose tissue (BAT) acts in mammals as a natural defense system against hypothermia, and its activation to a state of increased energy expenditure is believed to protect against the development of obesity. Even though the existence of BAT in adult humans has been widely appreciated1,2,3,4,5,6,7,8, its cellular origin and molecular identity remain elusive largely because of high cellular heterogeneity within various adipose tissue depots. To understand the nature of adult human brown adipocytes at single cell resolution, we isolated clonally derived adipocytes from stromal vascular fractions of adult human BAT from two individuals and globally analyzed their molecular signatures. We used RNA sequencing followed by unbiased genome-wide expression analyses and found that a population of uncoupling protein 1 (UCP1)-positive human adipocytes possessed molecular signatures resembling those of a recruitable form of thermogenic adipocytes (that is, beige adipocytes). In addition, we identified molecular markers that were highly enriched in UCP1-positive human adipocytes, a set that included potassium channel K3 (KCNK3) and mitochondrial tumor suppressor 1 (MTUS1). Further, we functionally characterized these two markers using a loss-of-function approach and found that KCNK3 and MTUS1 were required for beige adipocyte differentiation and thermogenic function. The results of this study present new opportunities for human BAT research, such as facilitating cell-based disease modeling and unbiased screens for thermogenic regulators.

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Acknowledgements

We acknowledge support from the National Institutes of Health (NIH) (DK087853 and DK097441), the UCSF Diabetes Research Center grant (DK63720), the UCSF Program for Breakthrough Biomedical Research program, the Pew Charitable Trust, and the Japan Science and Technology Agency (all to S.K.); and from the NIH (P50-GM60338) and the American Dental Association (1-14-TS-35) (both to L.S.S.). K.S. is supported by a fellowship from the Japan Society for the Promotion of Science. Y.H. is supported by the Manpei Suzuki Diabetes Foundation. I.H.N.L. is supported by the Dutch Heart Foundation.

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Author notes

  1. Si B Sonne & Miae Kim
    Present address: Present addresses: Department of Biology, University of Copenhagen, Copenhagen, Denmark (S.B.S.), East Coast Life Sciences Institute, Gangneung-Wonju National University, Gangneung, South Korea (M.K.).,
  2. Kosaku Shinoda and Ineke H N Luijten: These authors contributed equally to this work.

Authors and Affiliations

  1. Diabetes Center, University of California, San Francisco (UCSF), San Francisco, California, USA
    Kosaku Shinoda, Ineke H N Luijten, Yutaka Hasegawa, Haemin Hong, Si B Sonne, Miae Kim & Shingo Kajimura
  2. Department of Cell and Tissue Biology, UCSF, San Francisco, California, USA
    Kosaku Shinoda, Ineke H N Luijten, Yutaka Hasegawa, Haemin Hong, Si B Sonne, Miae Kim & Shingo Kajimura
  3. Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California, USA
    Kosaku Shinoda, Ineke H N Luijten, Yutaka Hasegawa, Haemin Hong, Si B Sonne, Miae Kim & Shingo Kajimura
  4. Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
    Ineke H N Luijten & Jan Nedergaard
  5. Joslin Diabetes Center, Boston, Massachusetts, USA
    Ruidan Xue, Aaron M Cypess & Yu-Hua Tseng
  6. Harvard Medical School, Boston, Massachusetts, USA
    Ruidan Xue, Aaron M Cypess & Yu-Hua Tseng
  7. Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas, USA
    Maria Chondronikola & Labros S Sidossis
  8. Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
    Maria Chondronikola & Labros S Sidossis
  9. Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
    Maria Chondronikola & Labros S Sidossis
  10. Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas, USA
    Maria Chondronikola & Labros S Sidossis

Authors

  1. Kosaku Shinoda
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  2. Ineke H N Luijten
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  3. Yutaka Hasegawa
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  4. Haemin Hong
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  5. Si B Sonne
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  6. Miae Kim
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  7. Ruidan Xue
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  8. Maria Chondronikola
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  9. Aaron M Cypess
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  10. Yu-Hua Tseng
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  11. Jan Nedergaard
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  12. Labros S Sidossis
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  13. Shingo Kajimura
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Contributions

K.S. and S.K. designed the experiments. K.S., I.H.N.L., Y.H., H.H., S.B.S., M.K. and S.K. performed the cellular experiments and analyzed the data. M.C., A.M.C., L.S.S. and Y.-H.T. provided adipose tissue samples. K.S., Y.H., H.H., R.X. and S.K. analyzed adipose tissue samples. K.S. and S.K. wrote the manuscript. All authors contributed to editing the manuscript. S.K. conceived and managed the project.

Corresponding author

Correspondence toShingo Kajimura.

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Shinoda, K., Luijten, I., Hasegawa, Y. et al. Genetic and functional characterization of clonally derived adult human brown adipocytes.Nat Med 21, 389–394 (2015). https://doi.org/10.1038/nm.3819

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