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Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat

Nature Medicine volume 19, pages 635–639 (2013)Cite this article

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Abstract

The imbalance between energy intake and expenditure is the underlying cause of the current obesity and diabetes pandemics. Central to these pathologies is the fat depot: white adipose tissue (WAT) stores excess calories, and brown adipose tissue (BAT) consumes fuel for thermogenesis using tissue-specific uncoupling protein 1 (UCP1)1,2. BAT was once thought to have a functional role in rodents and human infants only, but it has been recently shown that in response to mild cold exposure, adult human BAT consumes more glucose per gram than any other tissue3. In addition to this nonshivering thermogenesis, human BAT may also combat weight gain by becoming more active in the setting of increased whole-body energy intake4,5,6,7. This phenomenon of BAT-mediated diet-induced thermogenesis has been observed in rodents8 and suggests that activation of human BAT could be used as a safe treatment for obesity and metabolic dysregulation9. In this study, we isolated anatomically defined neck fat from adult human volunteers and compared its gene expression, differentiation capacity and basal oxygen consumption to different mouse adipose depots. Although the properties of human neck fat vary substantially between individuals, some human samples share many similarities with classical, also called constitutive, rodent BAT.

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Figure 1: Anatomical localization of adult human neck BAT.
Figure 2: Adult human neck BAT lineage tracing.
Figure 3: Adult human neck BAT expresses functional genes similarly to mouse iBAT, can be grown ex vivo from multiple adipose tissue depots and has an unstimulated energy expenditure similar to that of mouse iBAT.

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References

  1. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  Google Scholar 

  2. Richard, D. & Picard, F. Brown fat biology and thermogenesis. Front. Biosci. 16, 1233–1260 (2011).

    Article  CAS  Google Scholar 

  3. Orava, J. et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 14, 272–279 (2011).

    Article  CAS  Google Scholar 

  4. Wijers, S.L., Saris, W.H. & Marken Lichtenbelt, W.D. Individual thermogenic responses to mild cold and overfeeding are closely related. J. Clin. Endocrinol. Metab. 92, 4299–4305 (2007).

    Article  CAS  Google Scholar 

  5. van Marken Lichtenbelt, W.D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).

    CAS  PubMed  Google Scholar 

  6. 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 

  7. 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 

  8. Cannon, B. & Nedergaard, J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J. Exp. Biol. 214, 242–253 (2011).

    Article  Google Scholar 

  9. Vernochet, C., McDonald, M.E. & Farmer, S.R. Brown adipose tissue: a promising target to combat obesity. Drug News Perspect. 23, 409–417 (2010).

    Article  CAS  Google Scholar 

  10. Zingaretti, M.C. et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 23, 3113–3120 (2009).

    Article  CAS  Google Scholar 

  11. Svensson, P.A. et al. Gene expression in human brown adipose tissue. Int. J. Mol. Med. 27, 227–232 (2011).

    Article  CAS  Google Scholar 

  12. Cinti, S. Transdifferentiation properties of adipocytes in the adipose organ. Am. J. Physiol. Endocrinol. Metab. 297, E977–E986 (2009).

    Article  CAS  Google Scholar 

  13. Morrison, S.F. 2010 Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section: central neural pathways for thermoregulatory cold defense. J. Appl. Physiol. 110, 1137–1149 (2011).

    Article  CAS  Google Scholar 

  14. Smith, R.E. Thermoregulatory and adaptive behavior of brown adipose tissue. Science 146, 1686–1689 (1964).

    Article  CAS  Google Scholar 

  15. 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 

  16. Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).

    Article  CAS  Google Scholar 

  17. Schulz, T.J. et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc. Natl. Acad. Sci. USA 108, 143–148 (2011).

    Article  CAS  Google Scholar 

  18. Petrovic, N. et al. Chronic peroxisome proliferator-activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J. Biol. Chem. 285, 7153–7164 (2010).

    Article  CAS  Google Scholar 

  19. 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 

  20. Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).

    Article  CAS  Google Scholar 

  21. Waldén, T.B., Petrovic, N. & Nedergaard, J. PPARα does not suppress muscle-associated gene expression in brown adipocytes but does influence expression of factors that fingerprint the brown adipocyte. Biochem. Biophys. Res. Commun. 397, 146–151 (2010).

    Article  Google Scholar 

  22. 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 

  23. Heaton, J.M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35–39 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Foster, D.O. & Frydman, M.L. Nonshivering thermogenesis in the rat. II. Measurements of blood flow with microspheres point to brown adipose tissue as the dominant site of the calorigenesis induced by noradrenaline. Can. J. Physiol. Pharmacol. 56, 110–122 (1978).

    Article  CAS  Google Scholar 

  25. Virtanen, K.A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).

    Article  CAS  Google Scholar 

  26. Tchkonia, T. et al. Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns. Am. J. Physiol. Endocrinol. Metab. 292, E298–E307 (2007).

    Article  CAS  Google Scholar 

  27. Gesta, S., Tseng, Y.H. & Kahn, C.R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007).

    Article  CAS  Google Scholar 

  28. Yamamoto, Y. et al. Adipose depots possess unique developmental gene signatures. Obesity (Silver Spring) 18, 872–878 (2010).

    Article  CAS  Google Scholar 

  29. Leonardsson, G. et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc. Natl. Acad. Sci. USA 101, 8437–8442 (2004).

    Article  CAS  Google Scholar 

  30. Ravussin, E. & Galgani, J.E. The implication of brown adipose tissue for humans. Annu. Rev. Nutr. 31, 33–47 (2011).

    Article  CAS  Google Scholar 

  31. Lee, P., Swarbrick, M.M., Zhao, J.T. & Ho, K.K. Inducible brown adipogenesis of supraclavicular fat in adult humans. Endocrinology 152, 3597–3602 (2011).

    Article  CAS  Google Scholar 

  32. Tseng, Y.H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).

    Article  CAS  Google Scholar 

  33. Pisania, A. et al. Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab. Invest. 90, 1661–1675 (2010).

    Article  Google Scholar 

  34. Reich, M. et al. GenePattern 2.0. Nat. Genet. 38, 500–501 (2006).

    Article  CAS  Google Scholar 

  35. Tchkonia, T. et al. Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. Diabetes 55, 2571–2578 (2006).

    Article  CAS  Google Scholar 

  36. Steenhuis, P., Pettway, G.J. & Ignelzi, M.A. Cell surface expression of stem cell antigen-1 (Sca-1) distinguishes osteo-, chondro-, and adipoprogenitors in fetal mouse calvaria. Calcif. Tissue Int. 82, 44–56 (2008).

    Article  CAS  Google Scholar 

  37. Kiefer, F.W. et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat. Med. 18, 918–925 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants DK087317, DK081604, DK046200, DK077097 and P30 DK036836 from the National Institute of Diabetes and Digestive and Kidney Diseases KL2 RR025757 and the Clinical Translational Science Award UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources, Harvard Catalyst, The Harvard Clinical and Translational Science Center (NIH award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers), as well as the Harvard Stem Cell Institute and Eli Lilly Foundation. We thank Y.I. Chen and K.K. Kwong for the magnetic resonance imaging; K. Chaudhary for assistance in figure design; M. Mittleman, H. Keenan and E. Wilker for biostatistical advice; J. Skupien for advice on factor analysis; H. Sacks for insights into the role of brown fat in warming blood; C. Cahill at the Joslin Diabetes Center Microscopy Core for expertise in histology; M. Rourk and G. Smyth for assistance in conducting the rodent studies; the teams of operating room nurses for assistance in tissue collection; and C.R. Kahn for input in preparing this manuscript. Finally, we are grateful to our volunteers for their commitment to the studies.

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Author notes

  1. Aaron M Cypess and Andrew P White: These authors contributed equally to this work.

Authors and Affiliations

  1. Research Division, Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

    Aaron M Cypess, Cecile Vernochet, Tim J Schulz, Ruidan Xue, Christina A Sass, Tian Liang Huang, Carla Roberts-Toler, Lauren S Weiner, Cathy Sze, Nathan Truchan, Ashley R Holman, Marcelo A Mori & Yu-Hua Tseng

  2. Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Andrew P White, Aron T Chacko, Laura N Deschamps & Lindsay M Herder

  3. Harvard-Thorndike Clinical Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Allison L Glasgow

  4. Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Alina Gavrila

  5. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Per-Olof Hasselgren

  6. Research Division, Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

    Michael Molla

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  1. Aaron M Cypess
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Contributions

A.M.C., A.P.W., R.X. and Y.-H.T. designed the experiments. A.M.C., A.P.W., C.V., T.J.S., C.A.S. and Y.-H.T. wrote the manuscript. T.L.H. did immunohistochemistry. A.M.C., A.P.W., R.X., C.A.S., C.R.-T., L.S.W., C.S., A.T.C., L.N.D., L.M.H., N.T., A.L.G., A.R.H., A.G., P.-O.H., M.A.M. and M.M. did the human gene expression profiling. C.A.S., N.T. and M.A.M. did the mouse gene expression profiling. T.J.S. performed brown adipogenesis experiments. C.V. and C.A.S. performed bioenergenics experiments. All authors contributed to editing the manuscript.

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Correspondence to Aaron M Cypess.

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Competing interests

A.M.C. and Y.-H.T. are recipients of a sponsored research grant from Chugai Pharmaceutical Co., Ltd through Joslin Diabetes Center.

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Supplementary Figures 1 and 2 and Supplementary Tables 1–6 (PDF 4867 kb)

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Cypess, A., White, A., Vernochet, C. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 19, 635–639 (2013). https://doi.org/10.1038/nm.3112

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