Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Functional thermogenic beige adipogenesis is inducible in human neck fat

International Journal of Obesity volume 38, pages 170–176 (2014)Cite this article

Subjects

Abstract

Background:

Recent studies suggest human neck brown adipose tissue (BAT) to consist of ‘brown adipocyte (BA)-like’ or beige adipocytes. However, little is known about their thermogenic function. Within the beige adipocyte transcriptome, fibroblast growth factor-21 (FGF21) is a gene whose protein product acts as an adipokine, regulating cold-induced thermogenesis in animals. Here, we explored (i) the adipogenic potential, thermogenic function and FGF21 secretory capacity of beige adipocytes derived from human neck fat and (ii) the role of FGF21 in modulating adipose bioenergetics.

Methods:

Progenitors isolated from human cervical fat were differentiated into adipocytes with either a BA-like or white adipocyte (WA) phenotype. FGF21 secretion was measured by enzyme-linked immuosorbent assay. Real-time PCR/western blotting was used to determine cellular mRNA/protein levels. Extracellular flux bioanalyzer was used to quantify adipocyte oxygen consumption and fatty acid oxidation. Adipocyte heat production was measured by infrared thermography.

Results:

Under hormonal manipulation, primary human neck pre-adipocytes differentiated into adipocytes with either BA-like or WA phenotypes, on gene/protein and functional levels. BA-like cells expressed beige but not classic BA markers. During BA differentiation, FGF21 gene expression and secretion were increased, and were augmented following norepinephrine exposure (a cold mimic in vitro). Differentiated WA expressed β-klotho, a critical co-factor mediating FGF21 action. Treatment of WA with FGF21-induced UCP1 expression and increased oxygen consumption, respiratory uncoupling, norepinephrine-mediated thermogenesis, fatty acid oxidation and heat production, thus recapitulating the association between cold-induced FGF21 secretion and cold-induced thermogenesis in vivo.

Conclusion:

Beige adipocytes are thermogenic in humans. FGF21 is a beige adipokine capable of promoting a brown fat-like thermogenic program in WAs.

Significance:

This study provides first evidence of inducible functional thermogenic beige adipogenesis in human neck fat. FGF21 holds promise as a cold-induced beige adipokine with metabolic benefits of therapeutic relevance through browning of white adipose tissue.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009; 58: 1526–1531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360: 1500–1508.

    Article  CAS  PubMed  Google Scholar 

  3. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518–1525.

    Article  CAS  PubMed  Google Scholar 

  4. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360: 1509–1517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lee P, Zhao JT, Swarbrick MM, Gracie G, Bova R, Greenfield JR et al. High prevalence of brown adipose tissue in adult humans. J Clin Endocrinol Metab 2011; 96: 2450–2455.

    Article  CAS  PubMed  Google Scholar 

  6. Lee P, Greenfield JR, Ho KK, Fulham MJ . A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2010; 299: E601–E606.

    Article  CAS  PubMed  Google Scholar 

  7. Lee P, Swarbrick MM, Ho KK . Brown adipose tissue in adult humans: a metabolic renaissance. Endocr Rev 2013; 34: 413–438.

    Article  CAS  PubMed  Google Scholar 

  8. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J . Chronic PPAR{gamma} activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classical brown adipocytes. J Biol Chem 2010; 285: 7153–7164.

    Article  CAS  PubMed  Google Scholar 

  10. Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J . Recruited vs nonrecruited molecular signatures of brown, ‘brite,’ and white adipose tissues. Am J Physiol Endocrinol Metab 2012; 302: E19–E31.

    Article  CAS  PubMed  Google Scholar 

  11. Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 2012; 7: e49452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu J, Cohen P, Spiegelman BM . Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev 2013; 27: 234–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115: 1627–1635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG . Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 2011; 17: 736–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012; 26: 271–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011; 286: 12983–12990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin B, Haman F et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 2012; 122: 545–552.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lee P, Swarbrick MM, Zhao JT, Ho KK . Inducible brown adipogenesis of supraclavicular fat in adult humans. Endocrinology 2011; 152: 3597–3602.

    Article  CAS  PubMed  Google Scholar 

  19. Lee P, Greenfield JR, Ho KK . Hot fat in a cool man: infrared thermography and brown adipose tissue. Diabetes Obes Metab 2011; 13: 92–93.

    Article  CAS  PubMed  Google Scholar 

  20. Paulik MA, Buckholz RG, Lancaster ME, Dallas WS, Hull-Ryde EA, Weiel JE et al. Development of infrared imaging to measure thermogenesis in cell culture: thermogenic effects of uncoupling protein-2, troglitazone, and beta-adrenoceptor agonists. Pharm Res 1998; 15: 944–949.

    Article  CAS  PubMed  Google Scholar 

  21. Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ et al. betaKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012; 16: 387–393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R et al. BetaKlotho is required for metabolic activity of fibroblast growth factor 21. Proc Natl Acad Sci USA 2007; 104: 7432–7437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee P, Brychta RJ, Linderman J, Smith S, Chen KY, Celi FS . Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J Clin Endocrinol Metab 2013; 98: E98–102.

    Article  CAS  PubMed  Google Scholar 

  24. Potthoff MJ, Kliewer SA, Mangelsdorf DJ . Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev 2012; 26: 312–324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B 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 2009; 23: 3113–3120.

    Article  CAS  PubMed  Google Scholar 

  26. Jespersen NZ, Larsen TJ, Peijs L, Daugaard S, Homoe P, Loft A et al. A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metabolism 2013; 17: 798–805.

    Article  CAS  PubMed  Google Scholar 

  27. Nedergaard J, Cannon B . UCP1 mRNA does not produce heat. Biochim Biophys Acta 2013; 1831: 943–949.

    Article  CAS  PubMed  Google Scholar 

  28. Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 2013; 19: 635–639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K et al. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab 2010; 298: E1244–E1253.

    Article  CAS  PubMed  Google Scholar 

  30. Lee YH, Petkova AP, Mottillo EP, Granneman JG . In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab 2012; 15: 480–491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr Michael Sack and Dr Jie Liu from National Heart, Lung and Blood Institute, for advice on Seahorse bioanalyzer operations, and Dr Douglas Forrest, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, for helpful discussion and critical appraisal on the manuscript. Paul Lee is supported by the Australian NHMRC Early Career Fellowship, the RACP Foundation Diabetes Australia Fellowship, and the Bushell Travelling Fellowship. This study was supported by the Intramural Research Program of NIDDK: programs Z01-DK047057-02 and Z01-DK071044.

Author information

Authors and Affiliations

  1. Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    P Lee, C D Werner & F S Celi

  2. Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    E Kebebew

Authors
  1. P Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C D Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Kebebew
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F S Celi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Lee.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, P., Werner, C., Kebebew, E. et al. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes 38, 170–176 (2014). https://doi.org/10.1038/ijo.2013.82

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2013.82

Keywords

This article is cited by

Search

Advanced search

Quick links