Skip to main content

Thank you for visiting 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.

The different shades of fat


Our understanding of adipose tissue biology has progressed rapidly since the turn of the century. White adipose tissue has emerged as a key determinant of healthy metabolism and metabolic dysfunction. This realization is paralleled only by the confirmation that adult humans have heat-dissipating brown adipose tissue, an important contributor to energy balance and a possible therapeutic target for the treatment of metabolic disease. We propose that the development of successful strategies to target brown and white adipose tissues will depend on investigations that elucidate their developmental origins and cell-type-specific functional regulators.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Origins of white, beige and brown adipocytes.
Figure 2: Factors regulating white, and brown or beige adipogenesis.
Figure 3: Regulation of lipolysis and thermogenesis in adipocytes by the sympathetic nervous system.
Figure 4: Assessment of rodent brown and beige adipocyte markers in human adipose tissue.


  1. 1

    Lelliott, C. & Vidal-Puig, A. J. Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Int. J. Obes. Relat. Metab. Disord. 28, S22–S28 (2004).

    CAS  Google Scholar 

  2. 2

    Scherer, P. E. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55, 1537–1545 (2006).

    CAS  Google Scholar 

  3. 3

    Hany, T. F. et al. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur. J. Nucl. Med. Mol. Imaging 29, 1393–1398 (2002).

    Google Scholar 

  4. 4

    Nedergaard, J. et al. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).

    CAS  Google Scholar 

  5. 5

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

    CAS  Google Scholar 

  6. 6

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

    CAS  Google Scholar 

  7. 7

    Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009). Refs 5–7 confirmed the presence of metabolically active BAT in adult humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Saito, M. et al. High incidence of metabolically active brown adipose effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

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

    CAS  Google Scholar 

  10. 10

    Cannon, B. & Nedergaard, J. Thermogenesis challenges the adipostat hypothesis for body-weight control. Proc. Nutr. Soc. 68, 401–407 (2009).

    Google Scholar 

  11. 11

    Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203–209 (2009).

    CAS  Google Scholar 

  12. 12

    Lowell, B. B. et al. Development of obesity in transgenic mice after genetic ablation of adipose tissue. Nature 366, 740–742 (1993).

    ADS  CAS  Google Scholar 

  13. 13

    Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nature Med. 17, 200–205 (2011).

    CAS  PubMed  Google Scholar 

  14. 14

    Arbeeny, C. M., Meyers, D. S., Hillyer, D. E. & Bergquist, K. E. Metabolic alterations associated with the antidiabetic effect of β 3-adrenergic receptor agonists in obese mice. Am. J. Physiol. 268, E678–E684 (1995).

    CAS  Google Scholar 

  15. 15

    Rothwell, N. J. & Stock, M. J. Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour. Clin. Sci. 64, 19–23 (1983).

    CAS  Google Scholar 

  16. 16

    Loncar, D., Afzelius, B. A. & Cannon, B. Epididymal white adipose tissue after cold stress in rats. I. Nonmitochondrial changes. J. Ultrastruct. Mol. Struct. Res. 101, 109–122 (1988).

    CAS  Google Scholar 

  17. 17

    Young, P., Arch, J. R. & Ashwell, M. Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett. 167, 10–14 (1984).

    CAS  Google Scholar 

  18. 18

    Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012). This major study investigated the brown or beige phenotype of the adipocytes found in human supraclavicular BAT, and included a comprehensive gene expression analysis comparing rodent brown, beige and white adipocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Waldén, T. B. et al. Recruited vs. nonrecruited molecular signatures of brown,“brite,” and white adipose tissues. Am. J. Physiol. Endocrinol. Metab. 302, E19–E31 (2012).

    ADS  Google Scholar 

  20. 20

    Sharp, L. Z. et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS ONE 7, e49452 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

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

    CAS  Google Scholar 

  22. 22

    Shabalina, I. G. et al. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 5, 1196–1203 (2013).

    CAS  Google Scholar 

  23. 23

    Virtue, S. & Vidal-Puig, A. Adipose tissue expandability, lipotoxicity and the metabolic syndrome–an allostatic perspective. Biochim. Biophys. Acta 1801, 338–349 (2010).

  24. 24

    Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cells in vivo. Cell 135, 240–249 (2008).

    CAS  Google Scholar 

  25. 25

    Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Carobbio, S., Rosen, B. & Vidal-Puig, A. Adipogenesis: new insights into brown adipose tissue differentiation. J. Mol. Endocrinol. 51, T75–T85 (2013).

    CAS  Google Scholar 

  27. 27

    Seale, P. et al. Pax7 is required for the specification of myogenic satellite cells. Cell 102, 777–786 (2000).

    CAS  Google Scholar 

  28. 28

    Lepper, C. & Fan, C. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48, 424–436 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Yin, H. et al. MicroRNA-133 controls brown adipose determination in skeletal muscle satellite cells by targeting Prdm16. Cell Metab. 17, 210–224 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008). This study included a fate-mapping approach to identify the lineage origin of brown and white adipocytes, and identified PRDM16 as a 'cell-fate switch' that specifies a brown fat or muscle cell fate.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    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).

    ADS  CAS  Google Scholar 

  32. 32

    Walden, T. B., Timmons, J. A., Keller, P., Nedergaard, J. & Cannon, B. Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes. J. Cell. Physiol. 218, 444–449 (2009).

    CAS  Google Scholar 

  33. 33

    Sanchez-Gurmaches, J. et al. PTEN loss in the Myf5 lineage redistributes body fat and reveals subsets of white adipocytes that arise from Myf5 precursors. Cell Metab. 16, 348–362 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Shan, T. et al. Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues. J. Lipid Res. 54, 2214–2224 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Tran, K. V. et al. The vascular endothelium of the adipose tissue give rise to both white and brown fat cells. Cell Metab. 15, 222–229 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Gupta, R. K. et al. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial perivascular cells. Cell Metab. 15, 230–239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nature Cell Biol. 15, 302–308 (2013).

    CAS  Google Scholar 

  38. 38

    Digby, J. E. et al. Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes. Diabetes 47, 138–141 (1998).

    CAS  Google Scholar 

  39. 39

    Petrovic, N., Shabalina, I. G., Timmons, J. A., Cannon, B. & Nedergaard, J. Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARg agonist. Am. J. Physiol. Endocrinol. Metab. 295, E287–E296 (2008).

    CAS  Google Scholar 

  40. 40

    Rosenwald, M., Perdikari, A., Rülicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nature Cell Biol. 15, 659–667 (2013).

    CAS  Google Scholar 

  41. 41

    Wang, Q. A., Tao, C., Gupta, R. K. & Scherer, P. E. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nature Med. 19, 1338–1344 (2013). Refs 40 and 41 both used genetically engineered mouse models to identify the adult origins of beige cells recruited by cold exposure.

    Google Scholar 

  42. 42

    Lee, Y.-H., Petkova, A. P., Mottillo, E. P. & Granneman, J. G. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab. 15, 480–491 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Liu, W. et al. A heterogeneous lineage origin underlies the phenotypic and molecular differences of white and beige adipocytes. J. Cell Sci. 126, 3527–3532 (2013).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Hansen, J. B. & Kristiansen, K. Regulatory circuits controlling white versus brown adipocyte differentiation. Biochem. J. 398, 153–168 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Puigserver, P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-α. Int. J. Obes. 29, S5–S9 (2005).

    CAS  Google Scholar 

  46. 46

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).

    CAS  Google Scholar 

  48. 48

    Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    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).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Frescas, D., Valenti, L. & Accili, D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J. Biol. Chem. 280, 20589–20595 (2005).

    CAS  Google Scholar 

  51. 51

    Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

    ADS  CAS  PubMed  Google Scholar 

  52. 52

    Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    CAS  Google Scholar 

  53. 53

    Fulco, M. et al. Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol. Cell 12, 51–62 (2003).

    CAS  Google Scholar 

  54. 54

    Qiang, L. et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell 150, 620–632 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Trajkovski, M. & Lodish, H. MicroRNA networks regulate development of brown adipocytes. Trends Endocrinol. Metab. 24, 442–450 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Chen, Y. et al. miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nature Commun. 4, 1769 (2013).

    ADS  Google Scholar 

  57. 57

    Sun, L. & Trajkovski, M. MiR-27 orchestrates the transcriptional regulation of brown adipogenesis. Metabolism 63, 272–282 (2014).

    CAS  Google Scholar 

  58. 58

    Mori, M., Nakagami, H., Rodriguez-Araujo, G., Nimura, K. & Kaneda, Y. Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol. 10, e1001314 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Sun, L. et al. MiR-193b-365, a brown fat enriched microRNA cluster, is essential for brown fat differentiation. Nature Cell Biol. 13, 958–965 (2011).

    CAS  Google Scholar 

  60. 60

    Trajkovski, M., Ahmed, K., Esau, C. C. & Stoffel, M. MyomiR-133 regulates brown fat differentiation through Prdm16. Nature Cell Biol. 14, 1330–1335 (2012).

    CAS  Google Scholar 

  61. 61

    Liu, W. et al. miR-133a regulates adipocyte browning in vivo. PLoS Genet. 9, e1003626 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Wilcox, G. Insulin and insulin resistance. Clin. Biochem. Rev. 26, 19–39 (2005).

    PubMed  PubMed Central  Google Scholar 

  63. 63

    Geerling, J. J. et al. Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies. J. Lipid Res. 55, 180–189 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Collins, S. & Surwit, R. S. The β-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog. Horm. Res. 56, 309–328 (2001).

    CAS  Google Scholar 

  65. 65

    Schulz, T. J. & Tseng, Y.-H. Brown adipose tissue: development, metabolism and beyond. Biochem. J. 453, 167–178 (2013).

    CAS  Google Scholar 

  66. 66

    Schulz, T. J. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Torp-Pedersen, C. et al. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial. Eur. Heart J. 28, 2915–2923 (2007).

    Google Scholar 

  68. 68

    Arch, J. R. S. β3-adrenoceptor agonists: potential, pitfalls and progress. Eur. J. Pharmacol. 440, 99–107 (2002).

    CAS  Google Scholar 

  69. 69

    Cederberg, A. et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106, 563–573 (2001).

    CAS  Google Scholar 

  70. 70

    Grønning, L. M. et al. Reduced PDE4 expression and activity contributes to enhanced catecholamine-induced cAMP accumulation in adipocytes from FOXC2 transgenic mice. FEBS Lett. 580, 4126–4130 (2006).

    Google Scholar 

  71. 71

    Lidell, M. E. et al. The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function. Diabetes 60, 427–435 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Whittle, A. J. et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871–885 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Boon, M. R. et al. BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS ONE 8, e74083 (2013).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Villarroya, F. & Vidal-Puig, A. Beyond the sympathetic tone: the new brown fat activators. Cell Metab. 17, 638–643 (2013).

    CAS  Google Scholar 

  76. 76

    Hondares, E. et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J. Biol. Chem. 286, 12983–12990 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Fisher, F. M. et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Lafontan, M. et al. Control of lipolysis by natriuretic peptides and cyclic GMP. Trends Endocrinol. Metab. 19, 130–137 (2008).

    CAS  Google Scholar 

  79. 79

    Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Moreno-Aliaga, M. J. et al. Cardiotrophin-1 is a key regulator of glucose and lipid metabolism. Cell Metab. 14, 242–253 (2011).

    CAS  Google Scholar 

  81. 81

    Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

    ADS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Jones, S. A., Scheller, J. & Rose-John, S. Therapeutic strategies for the clinical blockade of IL-6 / gp130 signaling. J. Clin. Invest. 121, 3375–3383 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Roca-Rivada, A. et al. FNDC5/irisin is not only a myokine but also an adipokine. PLoS ONE 8, e60563 (2013).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Zhang, Y. et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 63, 514–525 (2014).

    CAS  Google Scholar 

  85. 85

    Wikstrom, J. D. et al. Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J. 33, 418–436 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Nguyen, K. D. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Xue, Y. et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab. 9, 99–109 (2009).

    CAS  Google Scholar 

  88. 88

    Vitali, A. et al. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J. Lipid Res. 53, 619–629 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Xue, Y. et al. FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue. Proc. Natl Acad. Sci. USA 105, 10167–10172 (2008).

    ADS  CAS  Google Scholar 

  90. 90

    Elias, I. et al. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes 61, 1801–1813 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Sun, K. et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc. Natl Acad. Sci. USA 109, 5874–5879 (2012). The authors of this study dissected the contribution of angiogenesis to WAT function and dysfunction during the development of obesity compared with a state of existing obesity.

    ADS  CAS  Google Scholar 

  92. 92

    Trayhurn, P., Wang, B. & Wood, I. S. Hypoxia and the endocrine and signalling role of white adipose tissue. Arch. Physiol. Biochem. 114, 267–276 (2008).

    CAS  Google Scholar 

  93. 93

    Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nature Rev. Immunol. 11, 85–97 (2011).

    CAS  Google Scholar 

  94. 94

    Kolonin, M. G., Saha, P. K., Chan, L., Pasqualini, R. & Arap, W. Reversal of obesity by targeted ablation of adipose tissue. Nature Med. 10, 625–632 (2004).

    CAS  Google Scholar 

  95. 95

    Rupnick, M. A. et al. Adipose tissue mass can be regulated through the vasculature. Proc. Natl Acad. Sci. USA 99, 10730–10735 (2002).

    ADS  CAS  Google Scholar 

  96. 96

    Okuno, A. et al. Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J. Clin. Invest. 101, 1354–1361 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    De Souza, C. J. et al. Effects of pioplitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 50, 1863–1871 (2001).

    CAS  Google Scholar 

  98. 98

    Kim, J. Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Yamauchi, T. et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Med. 7, 941–946 (2001).

    CAS  Google Scholar 

  100. 100

    De Souza, C. J. et al. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistence. Diabetes 50, 1863–1871 (2001).

    CAS  Google Scholar 

  101. 101

    Kusminski, C. M. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nature Methods 18, 1539–1549 (2012).

    CAS  Google Scholar 

  102. 102

    Khan, T. et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol. Cell. Biol. 29, 1575–1591 (2009).

    CAS  Google Scholar 

  103. 103

    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).

    CAS  Google Scholar 

  104. 104

    Lidell, M. E. et al. Evidence for two types of brown adipose tissue in humans. Nature Med. 19, 631–634 (2013). Infant interscapular BAT was found to express markers of canonical rodent brown adipocytes, indicating the presence of bona fide brown adipose tissue in humans.

    CAS  Google Scholar 

  105. 105

    Cypess, A. M. et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nature Med. 19, 635–639 (2013). In this gene expression analysis, adult human neck fat showed enrichment of rodent brown-adipocyte markers and rodent beige-adipocyte markers in distinct locations, suggesting the co-existence of brown and beige-like adipocytes in adult humans.

    CAS  Google Scholar 

  106. 106

    Cinti, S. et al. Immunohistochemical localization of leptin and uncoupling protein in white and brown adipose tissue. Endocrinology 138, 797–804 (1997).

    CAS  Google Scholar 

  107. 107

    Ouellet, V. et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J. Clin. Invest. 122, 545–552 (2012).

    PubMed  PubMed Central  Google Scholar 

  108. 108

    Lee, P. et al. High prevalence of brown adipose tissue in adult humans. J. Clin. Endocrinol. Metab. 96, 2450–2455 (2011).

    CAS  Google Scholar 

  109. 109

    Muzik, O. et al. 15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat. J. Nucl. Med. 54, 523–531 (2013).

    CAS  Google Scholar 

  110. 110

    Yoneshiro, T. et al. Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring) 19, 13–16 (2011).

    Google Scholar 

  111. 111

    Pfannenberg, C. et al. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes 59, 1789–1793 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Ouellet, V. et al. Outdoor temperture, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake of 18F-FDG-detected BAT in humans. J. Clin. Endocrinol. Metab. 96, 192–199 (2011).

    CAS  Google Scholar 

  113. 113

    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).

    Google Scholar 

  114. 114

    Symonds, M. E. et al. Thermal imaging to assess age-related changes of skin temperature within the supraclavicular region co-locating with brown adipose tissue in healthy children. J. Pediatr. 161, 892–898 (2012).

    Google Scholar 

  115. 115

    van der Lans, A. A. J. J. et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J. Clin. Invest. 123, 3395–3403 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Vijgen, G. H. E. J. et al. Increased oxygen consumption in human adipose tissue from the “brown adipose tissue” region. J. Clin. Endocrinol. Metab. 98, E1230–E1234 (2013).

    CAS  Google Scholar 

  118. 118

    Lee, P., Werner, C. D., Kebebew, E. & Celi, F. S. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int. J. Obes. 38, 170–176 (2014).

    Google Scholar 

  119. 119

    Sengenès, C., Berlan, M., De Glisezinski, I., Lafontan, M. & Galitzky, J. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J. 14, 1345–1351 (2000).

    Google Scholar 

  120. 120

    Lee, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 19, 302–309 (2014).

    CAS  Google Scholar 

  121. 121

    Lee, P. et al. 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. 98, E98–E102 (2013).

    CAS  Google Scholar 

  122. 122

    Ahfeldt, T. et al. Programming human pluripotent stem cells into white and brown adipocytes. Nature Cell Biol. 14, 209–219 (2012).

    CAS  Google Scholar 

  123. 123

    Nishio, M. et al. Production of functional classical brown adipocytes from human pluripotent stem cells using specific hemopoietin cocktail without gene transfer. Cell Metab. 16, 394–406 (2012). Refs 122 and 123 are pioneering studies in which brown adipocytes were generated from human embryonic stem cells and human induced pluripotent stem cells.

    CAS  Google Scholar 

  124. 124

    Gunawardana, S. C. & Piston, D. W. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 61, 674–682 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).

    CAS  Google Scholar 

Download references


We apologize to those whose work was not directly cited because of space constraints. The authors are supported by FP7 BetaBAT, BBSRC, BHF and MRC programme grants, Wellcome Trust, and Cambridge Overseas Trust.

Author information



Corresponding authors

Correspondence to Vivian Peirce or Antonio Vidal-Puig.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Peirce, V., Carobbio, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76–83 (2014).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing