Genetic and functional characterization of clonally derived adult human brown adipocytes (original) (raw)
- Letter
- Published: 16 March 2015
- Ineke H N Luijten1,2,3,4 na1,
- Yutaka Hasegawa1,2,3,
- Haemin Hong1,2,3,
- Si B Sonne1,2,3 nAff11,
- Miae Kim1,2,3 nAff11,
- Ruidan Xue5,6,
- Maria Chondronikola7,8,9,10,
- Aaron M Cypess5,6,
- Yu-Hua Tseng5,6,
- Jan Nedergaard4,
- Labros S Sidossis7,8,9,10 &
- …
- Shingo Kajimura1,2,3
Nature Medicine volume 21, pages 389–394 (2015)Cite this article
- 17k Accesses
- 325 Citations
- 96 Altmetric
- Metrics details
Subjects
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
Accession codes
Primary accessions
ArrayExpress
Referenced accessions
Gene Expression Omnibus
References
- Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
Article CAS Google Scholar - Ouellet, V. et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J. Clin. Endocrinol. Metab. 96, 192–199 (2011).
Article CAS Google Scholar - van Marken Lichtenbelt, W.D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
Article CAS Google Scholar - Yoneshiro, T. et al. Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity (Silver Spring) 19, 1755–1760 (2011).
Article Google Scholar - Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).
Article CAS Google Scholar - Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).
Article CAS Google Scholar - Virtanen, K.A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
Article CAS Google Scholar - Lidell, M.E. et al. Evidence for two types of brown adipose tissue in humans. Nat. Med. 19, 631–634 (2013).
Article CAS Google Scholar - Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
Article CAS Google Scholar - Atit, R. et al. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164–176 (2006).
Article CAS Google Scholar - Timmons, J.A. et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc. Natl. Acad. Sci. USA 104, 4401–4406 (2007).
Article CAS Google Scholar - Ohno, H., Shinoda, K., Ohyama, K., Sharp, L.Z. & Kajimura, S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504, 163–167 (2013).
Article CAS Google Scholar - Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19, 1252–1263 (2013).
Article CAS Google Scholar - Kajimura, S. & Saito, M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu. Rev. Physiol. 76, 225–249 (2014).
Article CAS Google Scholar - Waldén, T.B., Hansen, I.R., Timmons, J.A., Cannon, B. & Nedergaard, J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am. J. Physiol. Endocrinol. Metab. 302, E19–E31 (2012).
Article Google Scholar - 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 - Ohno, H., Shinoda, K., Spiegelman, B.M. & Kajimura, S. PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395–404 (2012).
Article CAS Google Scholar - Sharp, L.Z. et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS ONE 7, e49452 (2012).
Article CAS Google Scholar - Lee, P., Werner, C.D., Kebebew, E. & Celi, F.S. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int. J. Obes. (Lond). 38, 170–176 (2014).
Article Google Scholar - Jespersen, N.Z. et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab. 17, 798–805 (2013).
Article CAS Google Scholar - Cypess, A.M. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat. Med. 19, 635–639 (2013).
Article CAS Google Scholar - Villarroya, F. & Vidal-Puig, A. Beyond the sympathetic tone: the new brown fat activators. Cell Metab. 17, 638–643 (2013).
Article CAS Google Scholar - Tews, D. et al. Comparative gene array analysis of progenitor cells from human paired deep neck and subcutaneous adipose tissue. Mol. Cell. Endocrinol. 395, 41–50 (2014).
Article CAS Google Scholar - Long, J.Z. et al. A smooth muscle-like origin for beige adipocytes. Cell Metab. 19, 810–820 (2014).
Article CAS Google Scholar - Rajakumari, S. et al. EBF2 determines and maintains brown adipocyte identity. Cell Metab. 17, 562–574 (2013).
Article CAS Google Scholar - Schulz, T.J. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013).
Article CAS Google Scholar - Svensson, P.A. et al. Gene expression in human brown adipose tissue. Int. J. Mol. Med. 27, 227–232 (2011).
Article CAS Google Scholar - Søndergaard, E. et al. Chronic adrenergic stimulation induces brown adipose tissue differentiation in visceral adipose tissue. Diabet. Med. 32, e4–e8 (2015).
Article Google Scholar - Nouet, S. et al. Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. J. Biol. Chem. 279, 28989–28997 (2004).
Article CAS Google Scholar - Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014).
Article CAS Google Scholar - van der Lans, A.A. et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J. Clin. Invest. 123, 3395–3403 (2013).
Article CAS Google Scholar - Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408 (2013).
Article CAS Google Scholar - Lee, P. et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63, 3686–3698 (2014).
Article CAS Google Scholar - Trapnell, C. et al. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat. Biotechnol. 31, 46–53 (2013).
Article CAS Google Scholar - Irizarry, R.A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).
Article Google Scholar - Li, C. & Wong, W.H. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl. Acad. Sci. USA 98, 31–36 (2001).
Article CAS Google Scholar - Saeed, A.I. et al. TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34, 374–378 (2003).
Article CAS Google Scholar - Stöver, B.C. & Muller, K.F. TreeGraph 2: combining and visualizing evidence from different phylogenetic analyses. BMC Bioinformatics 11, 7 (2010).
Article Google Scholar - Huang, W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).
CAS Google Scholar - Inoue, M., Harada, K., Matsuoka, H., Sata, T. & Warashina, A. Inhibition of TASK1-like channels by muscarinic receptor stimulation in rat adrenal medullary cells. J. Neurochem. 106, 1804–1814 (2008).
CAS PubMed Google Scholar - Cohen, J. Statistical Power Analysis for the Behavioral Sciences (L. Erlbaum Associates, Hillsdale, N.J., 1988).
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.
Author information
Author notes
- 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.)., - Kosaku Shinoda and Ineke H N Luijten: These authors contributed equally to this work.
Authors and Affiliations
- 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 - 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 - 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 - Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
Ineke H N Luijten & Jan Nedergaard - Joslin Diabetes Center, Boston, Massachusetts, USA
Ruidan Xue, Aaron M Cypess & Yu-Hua Tseng - Harvard Medical School, Boston, Massachusetts, USA
Ruidan Xue, Aaron M Cypess & Yu-Hua Tseng - Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas, USA
Maria Chondronikola & Labros S Sidossis - Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA
Maria Chondronikola & Labros S Sidossis - Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
Maria Chondronikola & Labros S Sidossis - Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas, USA
Maria Chondronikola & Labros S Sidossis
Authors
- Kosaku Shinoda
You can also search for this author inPubMed Google Scholar - Ineke H N Luijten
You can also search for this author inPubMed Google Scholar - Yutaka Hasegawa
You can also search for this author inPubMed Google Scholar - Haemin Hong
You can also search for this author inPubMed Google Scholar - Si B Sonne
You can also search for this author inPubMed Google Scholar - Miae Kim
You can also search for this author inPubMed Google Scholar - Ruidan Xue
You can also search for this author inPubMed Google Scholar - Maria Chondronikola
You can also search for this author inPubMed Google Scholar - Aaron M Cypess
You can also search for this author inPubMed Google Scholar - Yu-Hua Tseng
You can also search for this author inPubMed Google Scholar - Jan Nedergaard
You can also search for this author inPubMed Google Scholar - Labros S Sidossis
You can also search for this author inPubMed Google Scholar - Shingo Kajimura
You can also search for this author inPubMed Google Scholar
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.
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
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
- Received: 16 October 2014
- Accepted: 06 February 2015
- Published: 16 March 2015
- Issue Date: April 2015
- DOI: https://doi.org/10.1038/nm.3819