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.

Brown adipose tissue as a secretory organ

Key Points

  • The activity of brown adipose tissue (BAT) is associated with protection against obesity and associated metabolic alterations such as insulin resistance

  • Experimental evidence indicates that BAT has systemic effects by secreting regulatory molecules in addition to its capacity to use metabolic substrates for thermogenesis

  • Brown and beige adipocytes secrete multiple autocrine and paracrine factors that control expansion and activity of BAT and the extent of browning of white adipose tissue

  • BAT releases endocrine factors that can target peripheral tissues such as white adipose tissue, liver, pancreas, heart and bone, as well as affect systemic metabolism by interacting with the CNS

Abstract

Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and experimental studies have associated BAT activity with protection against obesity and metabolic diseases, such as type 2 diabetes mellitus and dyslipidaemia. Active BAT is present in adult humans and its activity is impaired in patients with obesity. The ability of BAT to protect against chronic metabolic disease has traditionally been attributed to its capacity to utilize glucose and lipids for thermogenesis. However, BAT might also have a secretory role, which could contribute to the systemic consequences of BAT activity. Several BAT-derived molecules that act in a paracrine or autocrine manner have been identified. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced. Additionally, BAT can release regulatory molecules that act on other tissues and organs. This secretory capacity of BAT is thought to be involved in the beneficial effects of BAT transplantation in rodents. Fibroblast growth factor 21, IL-6 and neuregulin 4 are among the first BAT-derived endocrine factors to be identified. In this Review, we discuss the current understanding of the regulatory molecules (the so-called brown adipokines or batokines) that are released by BAT that influence systemic metabolism and convey the beneficial metabolic effects of BAT activation. The identification of such adipokines might also direct drug discovery approaches for managing obesity and its associated chronic metabolic diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The autocrine and paracrine factors released by brown and beige adipocytes.
Figure 2: BMPs in brown and beige adipogenesis and function.
Figure 3: Putative batokines and target organs.

References

  1. 1

    Ricquier, D. & Bouillaud, F. Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance. J. Physiol. 15, 3–10 (2000).

    Google Scholar 

  2. 2

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

    CAS  PubMed  Google Scholar 

  3. 3

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

    CAS  PubMed  Google Scholar 

  4. 4

    Bletz, M. J. & Enerback, S. Human brown adipose tissue: what we have learned so far. Diabetes 64, 2352–2360 (2015).

    Google Scholar 

  5. 5

    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).

    CAS  PubMed  Google Scholar 

  6. 6

    Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

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

    CAS  PubMed  Google Scholar 

  8. 8

    Guerra, C., Koza, R. A., Yamashita, H., Walsh, K. & Kozak, L. P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Kazak, L. et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163, 643–655 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Labbe, S. M. et al. Metabolic activity of brown, “beige” and white adipose tissues in response to chronic adrenergic stimulation in male mice. Am. J. Physiol. Endocrinol. Metab. 311, E260–E268 (2016).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Nedergaard, J. & Cannon, B. The browning of white adipose tissue: some burning issues. Cell Metab. 20, 396–407 (2014).

    CAS  PubMed  Google Scholar 

  12. 12

    Friedman, J. 20 Years of leptin: leptin at 20: an overview. J. Endocrinol. 223, T1–T8 (2014).

    CAS  PubMed  Google Scholar 

  13. 13

    Ortega, M. T., Xie, L., Mora, S. & Chapes, S. K. Evaluation of macrophage plasticity in brown and white adipose tissue. Cell. Immunol. 271, 124–133 (2011).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Nechad, M., Ruka, E. & Thibault, J. Production of nerve growth factor by brown fat in culture: relation with the in vivo developmental stage of the tissue. Comp. Biochem. Physiol. Comp. Physiol. 107, 381–388 (1994).

    CAS  PubMed  Google Scholar 

  15. 15

    Nisoli, E., Tonello, C., Benarese, M., Liberini, P. & Carruba, M. O. Expression of nerve growth factor in brown adipose tissue: implications for thermogenesis and obesity. Endocrinology 137, 495–503 (1996).

    CAS  Google Scholar 

  16. 16

    Yamashita, H. et al. Basic fibroblast growth factor (bFGF) contributes to the enlargement of brown adipose tissue during cold acclimation. Pflugers Arch. 428, 352–356 (1994).

    CAS  PubMed  Google Scholar 

  17. 17

    Bartness, T. J., Vaughan, C. H. & Song, C. K. Sympathetic and sensory innervation of brown adipose tissue. Int. J. Obes. (Lond.). 34 (Suppl. 1), S36–S42 (2010).

    PubMed Central  Google Scholar 

  18. 18

    Bukowiecki, L., Collet, A. J., Follea, N., Guay, G. & Jahjah, L. Brown adipose tissue hyperplasia: a fundamental mechanism of adaptation to cold and hyperphagia. Am. J. Physiol. 242, E353–E359 (1982).

    CAS  PubMed  Google Scholar 

  19. 19

    Asano, A., Kimura, K. & Saito, M. Cold-induced mRNA expression of angiogenic factors in rat brown adipose tissue. J. Vet. Med. Sci. 61, 403–409 (1999).

    CAS  PubMed  Google Scholar 

  20. 20

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

    CAS  PubMed  Google Scholar 

  21. 21

    Foster, D. O. & Frydman, M. L. Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can. J. Physiol. Pharmacol. 57, 257–270 (1979).

    CAS  PubMed  Google Scholar 

  22. 22

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

    CAS  PubMed  Google Scholar 

  23. 23

    Sun, K. et al. Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Mol. Metab. 3, 474–483 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Mahdaviani, K., Chess, D., Wu, Y., Shirihai, O. & Aprahamian, T. R. Autocrine effect of vascular endothelial growth factor-A is essential for mitochondrial function in brown adipocytes. Metabolism 65, 26–35 (2016).

    CAS  PubMed  Google Scholar 

  25. 25

    Hansen, I. R., Jansson, K. M., Cannon, B. & Nedergaard, J. Contrasting effects of cold acclimation versus obesogenic diets on chemerin gene expression in brown and brite adipose tissues. Biochim. Biophys. Acta 1841, 1691–1699 (2014).

    CAS  PubMed  Google Scholar 

  26. 26

    Rourke, J. L., Muruganandan, S., Dranse, H. J., McMullen, N. M. & Sinal, C. J. Gpr1 is an active chemerin receptor influencing glucose homeostasis in obese mice. J. Endocrinol. 222, 201–215 (2014).

    CAS  PubMed  Google Scholar 

  27. 27

    Mattern, A., Zellmann, T. & Beck-Sickinger, A. G. Processing, signaling, and physiological function of chemerin. IUBMB Life 66, 19–26 (2014).

    CAS  PubMed  Google Scholar 

  28. 28

    Vegiopoulos, A. et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328, 1158–1161 (2010).

    CAS  PubMed  Google Scholar 

  29. 29

    Virtue, S. et al. A new role for lipocalin prostaglandin D synthase in the regulation of brown adipose tissue substrate utilization. Diabetes 61, 3139–3147 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Tanaka, T. et al. Lipocalin-type prostaglandin D synthase (β-trace) is a newly recognized type of retinoid transporter. J. Biol. Chem. 272, 15789–15795 (1997).

    CAS  PubMed  Google Scholar 

  31. 31

    Garcia-Alonso, V. & Claria, J. Prostaglandin E2 signals white-to-brown adipogenic differentiation. Adipocyte 3, 290–296 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Nisoli, E., Tonello, C., Briscini, L. & Carruba, M. O. Inducible nitric oxide synthase in rat brown adipocytes: implications for blood flow to brown adipose tissue. Endocrinology 138, 676–682 (1997).

    CAS  PubMed  Google Scholar 

  33. 33

    Roberts, L. D. et al. Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway. Diabetes 64, 471–484 (2015).

    CAS  PubMed  Google Scholar 

  34. 34

    Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014).

    CAS  PubMed  Google Scholar 

  35. 35

    Fedorenko, A., Lishko, P. V. & Kirichok, Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151, 400–413 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Whittle, A. J. et al. Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. Nat. Commun. 6, 8951 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Krott, L. M. et al. Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation. J. Lipid Res. 57, 464–473 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Boon, M. R. et al. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity. FASEB J. 28, 5361–5375 (2014).

    CAS  PubMed  Google Scholar 

  39. 39

    Klepac, K. et al. The Gq signalling pathway inhibits brown and beige adipose tissue. Nat. Commun. 7, 10895 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Modica, S. & Wolfrum, C. Bone morphogenic proteins signaling in adipogenesis and energy homeostasis. Biochim. Biophys. Acta 1831, 915–923 (2013).

    CAS  PubMed  Google Scholar 

  41. 41

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Qian, S. W. et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc. Natl Acad. Sci. USA 110, E798–E807 (2013).

    CAS  PubMed  Google Scholar 

  43. 43

    Zamani, N. & Brown, C. W. Emerging roles for the transforming growth factor-β superfamily in regulating adiposity and energy expenditure. Endocr. Rev. 32, 387–403 (2011).

    CAS  PubMed  Google Scholar 

  44. 44

    Yoshida, H. et al. Regulation of brown adipogenesis by the Tgf-β family: involvement of Srebp1c in Tgf-β- and Activin-induced inhibition of adipogenesis. Biochim. Biophys. Acta 1830, 5027–5035 (2013).

    CAS  PubMed  Google Scholar 

  45. 45

    Schleinitz, D. et al. Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio. Int. J. Obes. (Lond.) 38, 120–125 (2014).

    CAS  Google Scholar 

  46. 46

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

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    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).

    CAS  PubMed  Google Scholar 

  48. 48

    Seale, P., Kajimura, S. & Spiegelman, B. M. Transcriptional control of brown adipocyte development and physiological function—of mice and men. Genes Dev. 23, 788–797 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Townsend, K. L. et al. Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake. Antioxid. Redox Signal 19, 243–257 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Townsend, K. L. et al. Bone morphogenetic protein 7 (BMP7) reverses obesity and regulates appetite through a central mTOR pathway. FASEB J. 26, 2187–2196 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Bowers, R. R. & Lane, M. D. A role for bone morphogenetic protein-4 in adipocyte development. Cell Cycle 6, 385–389 (2007).

    CAS  PubMed  Google Scholar 

  52. 52

    Xue, R. et al. Role of bone morphogenetic protein 4 in the differentiation of brown fat-like adipocytes. Am. J. Physiol. Endocrinol. Metab. 306, E363–E372 (2014).

    CAS  PubMed  Google Scholar 

  53. 53

    Elsen, M. et al. BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells. Am. J. Physiol. Cell Physiol. 306, C431–C440 (2014).

    CAS  PubMed  Google Scholar 

  54. 54

    Gustafson, B. et al. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes 64, 1670–1681 (2015).

    CAS  PubMed  Google Scholar 

  55. 55

    Fasshauser, M. & Blüher, M. Adipokines in health and disease. Trends Pharmacol. Sci. 36, 461–470 (2015).

    Google Scholar 

  56. 56

    Oryan, A., Alidadi, S., Moshiri, A. & Bigham-Sadegh, A. Bone morphogenetic proteins: a powerful osteoinductive compound with non-negligible side effects and limitations. Biofactors 40, 459–481 (2014).

    CAS  PubMed  Google Scholar 

  57. 57

    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 

  58. 58

    Grefhorst, A. et al. Estrogens increase expression of bone morphogenetic protein 8b in brown adipose tissue of mice. Biol. Sex. Differ. 6, 7 (2015).

    PubMed  PubMed Central  Google Scholar 

  59. 59

    Hinoi, E. et al. Growth differentiation factor-5 promotes brown adipogenesis in systemic energy expenditure. Diabetes 63, 162–175 (2014).

    CAS  PubMed  Google Scholar 

  60. 60

    Kuo, M. M. et al. BMP-9 as a potent brown adipogenic inducer with anti-obesity capacity. Biomaterials 35, 3172–3179 (2014).

    CAS  PubMed  Google Scholar 

  61. 61

    Koncarevic, A. et al. A novel therapeutic approach to treating obesity through modulation of TGFβ signaling. Endocrinology 153, 3133–3146 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Fournier, B. et al. Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism. Mol. Cell. Biol. 32, 2871–2879 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Steculorum, S. M. et al. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165, 125–138 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Braga, M., Pervin, S., Norris, K., Bhasin, S. & Singh, R. Inhibition of in vitro and in vivo brown fat differentiation program by myostatin. Obesity (Silver Spring) 21, 1180–1188 (2013).

    CAS  Google Scholar 

  66. 66

    Braga, M. et al. Follistatin promotes adipocyte differentiation, browning, and energy metabolism. J. Lipid Res. 55, 375–384 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Shoelson, S. E., Lee, J. & Goldfine, A. B. Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

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

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Nisoli, E. et al. Tumor necrosis factor α mediates apoptosis of brown adipocytes and defective brown adipocyte function in obesity. Proc. Natl Acad. Sci. USA 97, 8033–8038 (2000).

    CAS  PubMed  Google Scholar 

  71. 71

    Goto, T. et al. Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes. Cytokine 77, 107–114 (2016).

    CAS  PubMed  Google Scholar 

  72. 72

    Masaki, T. et al. Tumor necrosis factor-α regulates in vivo expression of the rat UCP family differentially. Biochim. Biophys. Acta 1436, 585–592 (1999).

    CAS  PubMed  Google Scholar 

  73. 73

    Romanatto, T. et al. Deletion of tumor necrosis factor-α receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. J. Biol. Chem. 284, 36213–36222 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Burysek, L. & Houstek, J. β-Adrenergic stimulation of interleukin-1α and interleukin-6 expression in mouse brown adipocytes. FEBS Lett. 411, 83–86 (1997).

    CAS  PubMed  Google Scholar 

  75. 75

    Hinoi, E., Iezaki, T., Ozaki, K. & Yoneda, Y. Nuclear factor-κB is a common upstream signal for growth differentiation factor-5 expression in brown adipocytes exposed to pro-inflammatory cytokines and palmitate. Biochem. Biophys. Res. Commun. 452, 974–979 (2014).

    CAS  PubMed  Google Scholar 

  76. 76

    Brestoff, J. R. et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015).

    CAS  PubMed  Google Scholar 

  77. 77

    Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Lee, M. W. et al. Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160, 74–87 (2015).

    CAS  PubMed  Google Scholar 

  80. 80

    Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Hui, X. et al. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab. 22, 279–290 (2015).

    CAS  PubMed  Google Scholar 

  82. 82

    Silva, J. E. & Larsen, P. R. Potential of brown adipose tissue type II thyroxine 5′-deiodinase as a local and systemic source of triiodothyronine in rats. J. Clin. Invest. 76, 2296–2305 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Silva, J. E. & Larsen, P. R. Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 305, 712–713 (1983).

    CAS  PubMed  Google Scholar 

  84. 84

    Bianco, A. C. & Silva, J. E. Optimal response of key enzymes and uncoupling protein to cold in BAT depends on local T3 generation. Am. J. Physiol. 253, E255–E263 (1987).

    CAS  PubMed  Google Scholar 

  85. 85

    Fernandez, J. A., Mampel, T., Villarroya, F. & Iglesias, R. Direct assessment of brown adipose tissue as a site of systemic tri-iodothyronine production in the rat. Biochem. J. 243, 281–284 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    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 

  87. 87

    Gunawardana, S. C. & Piston, D. W. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am. J. Physiol. Endocrinol. Metab. 308, E1043–E1055 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Liu, X. et al. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res. 23, 851–854 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

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

    CAS  PubMed  Google Scholar 

  90. 90

    Liu, X. et al. Brown adipose tissue transplantation reverses obesity in ob/ob mice. Endocrinology 156, 2461–2469 (2015).

    CAS  PubMed  Google Scholar 

  91. 91

    Zhu, Z. et al. Enhanced sympathetic activity in mice with brown adipose tissue transplantation (transBATation). Physiol. Behav. 125, 21–29 (2014).

    CAS  PubMed  Google Scholar 

  92. 92

    Stanford, K. I. et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Diabetes 64, 2002–2014 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Min, S. Y. et al. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat. Med. 22, 312–318 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Thoonen, R. et al. Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy. J. Mol. Cell. Cardiol. 84, 202–211 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Yuan, X. et al. Brown adipose tissue transplantation ameliorates polycystic ovary syndrome. Proc. Natl Acad. Sci. USA 113, 2708–2713 (2016).

    CAS  PubMed  Google Scholar 

  96. 96

    Giralt, M., Gavalda-Navarro, A. & Villarroya, F. Fibroblast growth factor-21, energy balance and obesity. Mol. Cell. Endocrinol. 418, 66–73 (2015).

    CAS  PubMed  Google Scholar 

  97. 97

    Markan, K. R. et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63, 4057–4066 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Chartoumpekis, D. V. et al. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol. Med. 17, 736–740 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    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 

  100. 100

    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 

  101. 101

    Hondares, E. et al. Hepatic FGF21 expression is induced at birth via PPARα in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 11, 206–212 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Keipert, S. et al. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol. Metab. 4, 537–542 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Samms, R. J. et al. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep. 11, 991–999 (2015).

    CAS  PubMed  Google Scholar 

  104. 104

    Keipert, S. et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am. J. Physiol. Endocrinol. Metab. 306, E469–E482 (2014).

    CAS  PubMed  Google Scholar 

  105. 105

    Ribas, F., Villarroya, J., Hondares, E., Giralt, M. & Villarroya, F. FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling. Biochem. J. 463, 191–199 (2014).

    CAS  PubMed  Google Scholar 

  106. 106

    Suomalainen, A. et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 10, 806–818 (2011).

    CAS  PubMed  Google Scholar 

  107. 107

    Veniant, M. M. et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab. 21, 731–738 (2015).

    CAS  PubMed  Google Scholar 

  108. 108

    Ikeda, S. I. et al. Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle. Biochem. Biophys. Res. Commun. 473, 947–952 (2016).

    CAS  PubMed  Google Scholar 

  109. 109

    Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423–430 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Knudsen, J. G. et al. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLoS ONE 9, e84910 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. 111

    Rosell, M. et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am. J. Physiol. Endocrinol. Metab. 306, E945–E964 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Wang, G. X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Rahman, S. et al. Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton. Endocrinology 154, 2687–2701 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356–362 (2005).

    CAS  PubMed  Google Scholar 

  115. 115

    Rosell, M. et al. Peroxisome proliferator-activated receptors-α and -γ, and cAMP-mediated pathways, control retinol-binding protein-4 gene expression in brown adipose tissue. Endocrinology 153, 1162–1173 (2012).

    CAS  PubMed  Google Scholar 

  116. 116

    Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).

    CAS  PubMed  Google Scholar 

  117. 117

    Fu, Z., Yao, F., Abou-Samra, A. B. & Zhang, R. Lipasin, thermoregulated in brown fat, is a novel but atypical member of the angiopoietin-like protein family. Biochem. Biophys. Res. Commun. 430, 1126–1131 (2013).

    CAS  PubMed  Google Scholar 

  118. 118

    Zhang, R. & Abou-Samra, A. B. Emerging roles of lipasin as a critical lipid regulator. Biochem. Biophys. Res. Commun. 432, 401–405 (2013).

    CAS  PubMed  Google Scholar 

  119. 119

    Yi, P., Park, J. S. & Melton, D. A. Betatrophin: a hormone that controls pancreatic β cell proliferation. Cell 153, 747–758 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Gusarova, V. et al. ANGPTL8/betatrophin does not control pancreatic β cell expansion. Cell 159, 691–696 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Verdeguer, F. et al. Brown adipose YY1 deficiency activates expression of secreted proteins linked to energy expenditure and prevents diet-induced obesity. Mol. Cell. Biol. 36, 184–196 (2015).

    PubMed  PubMed Central  Google Scholar 

  122. 122

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

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Walden, 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).

    CAS  PubMed  Google Scholar 

  124. 124

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

    CAS  PubMed  Google Scholar 

  125. 125

    Dushay, J. et al. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139, 456–463 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Hondares, E. et al. Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue. Metabolism 63, 312–317 (2014).

    CAS  PubMed  Google Scholar 

  127. 127

    Di Franco, A. et al. Searching for classical brown fat in humans: development of a novel human fetal brown stem cell model. Stem Cells 34, 1679–1691 (2016).

    CAS  PubMed  Google Scholar 

  128. 128

    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  PubMed  Google Scholar 

  129. 129

    Hanssen, M. J. et al. Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci. Rep. 5, 10275 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    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  PubMed  Google Scholar 

  131. 131

    Tran, T. T. & Kahn, C. R. Transplantation of adipose tissue and stem cells: role in metabolism and disease. Nat. Rev. Endocrinol. 6, 195–213 (2010).

    PubMed  PubMed Central  Google Scholar 

  132. 132

    Svensson, K. J. et al. A secreted Slit2 fragment regulates adipose tissue thermogenesis and metabolic function. Cell Metab. 23, 454–466 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the support of grants SAF2014-55725 from the Ministerio de Ciencia e Innovación (MINECO) and PI14/00063 from the Instituto de Salud Carlos III, Spain, co-financed by the European Regional Development Fund (ERDF), and the European Community Seventh Framework Program (FP7 BetaBat).

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the preparation of this article.

Corresponding authors

Correspondence to Francesc Villarroya or Marta Giralt.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Secreted factors expressed in BAT and/or brown/beige adipocytes in association with differentiation and/or thermogenic activation (PDF 128 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Villarroya, F., Cereijo, R., Villarroya, J. et al. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol 13, 26–35 (2017). https://doi.org/10.1038/nrendo.2016.136

Download citation

Further reading

Search

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