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.

  • Review
  • Published:

Reviews

Non-sympathetic control of brown adipose tissue

Abstract

The thermogenic activity of brown adipose tissue (BAT) in the organism is tightly regulated through different processes, from short-term induction of uncoupling protein-1-mediated mitochondrial proton conductance to complex processes of BAT recruitment, and appearance of the beige/brite adipocytes in white adipose tissue (WAT), the so-called browning process. The sympathetic nervous system is classically recognized as the main mediator of BAT activation. However, novel factors capable of activating BAT through non-sympathetic mechanisms have been recently identified. Among them are members of the bone morphogenetic protein family, with likely autocrine actions, and activators of nuclear hormone receptors, especially vitamin A derivatives. Multiple endocrine factors released by peripheral tissues that act on BAT have also been identified. Some are natriuretic peptides of cardiac origin, whereas others include irisin, originating in skeletal muscle, and fibroblast growth factor-21, mainly produced in the liver. These factors have cell-autonomous effects in brown adipocytes, but indirect effects in vivo that modulate sympathetic activity toward BAT cannot be excluded. Moreover, these factors can affect to different extents such as the activation of existing BAT, the induction of browning in WAT or both. The identification of non-sympathetic controllers of BAT activity is of special biomedical interest as a prerequisite for developing pharmacological tools that influence BAT activity without the side effects of sympathomimetics.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Rial E, González-Barroso MM . Physiological regulation of the transport activity in the uncoupling proteins UCP1 and UCP2. Biochim Biophys Acta 2001; 1504: 70–81.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Young P, Arch JR, Ashwell M . Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett 1984; 167: 10–14.

    Article  CAS  PubMed  Google Scholar 

  5. Wu J, Boström 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 

  6. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J . Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) 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 2010; 285: 7153–7164.

    Article  CAS  PubMed  Google Scholar 

  7. Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Pénicaud L et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 1992; 103 (Pt 4): 931–942.

    CAS  PubMed  Google Scholar 

  8. Enerbäck S . Human brown adipose tissue. Cell Metab 2010; 11: 248–252.

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Yen M, Ewald MB . Toxicity of weight loss agents. J Med Toxicol 2012; 8: 145–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 2008; 454: 1000–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 2013; 495: 379–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Qian SW, Tang Y, Li X, Liu Y, Zhang YY, Huang HY et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA 2013; 110: E798–E807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hinoi E, Nakamura Y, Takada S, Fujita H, Iezaki T, Hashizume S et al. Growth differentiation factor-5 promotes brown adipogenesis in systemic energy expenditure. Diabetes 2014; 63: 162–175.

    Article  CAS  PubMed  Google Scholar 

  15. Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vázquez MJ et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 2012; 149: 871–885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vegiopoulos A, Müller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 2010; 328: 1158–1161.

    Article  CAS  PubMed  Google Scholar 

  17. Madsen L, Pedersen LM, Lillefosse HH, Fjaere E, Bronstad I, Hao Q et al. UCP1 induction during recruitment of brown adipocytes in white adipose tissue is dependent on cyclooxygenase activity. PLoS One 2010; 5: e11391.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. García-Alonso V, López-Vicario C, Titos E, Morán-Salvador E, González-Périz A, Rius B et al. Coordinate functional regulation between microsomal prostaglandin E synthase-1 (mPGES-1) and peroxisome proliferator-activated receptor γ (PPARγ) in the conversion of white-to-brown adipocytes. J Biol Chem 2013; 288: 28230–28242.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Bonet ML, Oliver P, Palou A . Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim Biophys Acta 2013; 1831: 969–985.

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Del Mar Gonzalez-Barroso M, Ricquier D, Cassard-Doulcier AM . The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research. Obes Rev 2000; 1: 61–72.

    Article  CAS  PubMed  Google Scholar 

  22. de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW et al. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 2001; 108: 1379–1385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Silva JE, Larsen PR . Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 1983; 305: 712–713.

    Article  CAS  PubMed  Google Scholar 

  24. Alvarez R, de Andrés J, Yubero P, Viñas O, Mampel T, Iglesias R et al. A novel regulatory pathway of brown fat thermogenesis. Retinoic acid is a transcriptional activator of the mitochondrial uncoupling protein gene. J Biol Chem 1995; 270: 5666–5673.

    Article  CAS  PubMed  Google Scholar 

  25. Mercader J, Ribot J, Murano I, Felipe F, Cinti S, Bonet ML et al. Remodeling of white adipose tissue after retinoic acid administration in mice. Endocrinology 2004; 147: 5325–5332.

    Article  CAS  Google Scholar 

  26. Kiefer FW, Vernochet C, O'Brien P, Spoerl S, Brown JD, Nallamshetty S et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med 2012; 18: 918–925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Villarroya F, Iglesias R, Giralt M . Retinoids and retinoid receptors in the control of energy balance: novel pharmacological strategies in obesity and diabetes. Curr Med Chem 2006; 11: 795–805.

    Article  Google Scholar 

  28. Tai TA, Jennermann C, Brown KK, Oliver BB, MacGinnitie MA, Wilkison WO et al. Activation of the nuclear receptor peroxisome proliferator-activated receptor gamma promotes brown adipocyte differentiation. J Biol Chem 1996; 271: 29909–29914.

    Article  CAS  PubMed  Google Scholar 

  29. Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M . Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J Biol Chem 2010; 276: 1486–1493.

    Article  Google Scholar 

  30. Ohno H, Shinoda K, Spiegelman BM, Kajimura S . PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 2012; 15: 395–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sell H, Berger JP, Samson P, Castriota G, Lalonde J, Deshaies Y et al. Peroxisome proliferator-activated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice. Endocrinology 2004; 145: 3925–3934.

    Article  CAS  PubMed  Google Scholar 

  32. Valmaseda A, Carmona MC, Barberá MJ, Viñas O, Mampel T, Iglesias R et al. Opposite regulation of PPAR-alpha and -gamma gene expression by both their ligands and retinoic acid in brown adipocytes. Mol Cell Endocrinol 1999; 154: 101–109.

    Article  CAS  PubMed  Google Scholar 

  33. Xue B, Coulter A, Rim JS, Koza RA, Kozak LP . Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots. Mol Cell Biol 2005; 25: 8311–8322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y et al. Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. J Mol Cell Biol 2012; 4: 88–96.

    Article  CAS  PubMed  Google Scholar 

  35. Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A et al. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol 2013; 383: 137–146.

    Article  CAS  PubMed  Google Scholar 

  36. Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS et al. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell 2012; 151: 96–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Upadhyay SK, Eckel-Mahan KL, Mirbolooki MR, Tjong I, Griffey SM, Schmunk G et al. Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance. Proc Natl Acad Sci USA 2013; 110: E2239–E2248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 2012; 122: 1022–1036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moreno-Aliaga MJ, Pérez-Echarri N, Marcos-Gómez B, Larequi E, Gil-Bea FJ, Viollet B et al. Cardiotrophin-1 is a key regulator of glucose and lipid metabolism. Cell Metab 2011; 14: 242–253.

    Article  CAS  PubMed  Google Scholar 

  40. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463–468.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C et al. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes 2012; 61: 2753–2762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 2004; 145: 2594–2603.

    Article  CAS  PubMed  Google Scholar 

  43. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439: 484–489.

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F . Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 2010; 11: 206–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Díaz-Delfín J, Hondares E, Iglesias R, Giralt M, Caelles C, Villarroya F . TNF-α represses β-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway. Endocrinology 2012; 153: 4238–4245.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K et al. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 2010; 59: 1817–1824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013; 19: 1147–1152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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 

  51. Hondares E, Gallego-Escuredo JM, Flachs P, Frontini A, Cereijo R, Goday A et al. Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue. Metabolism 2013; 63: 312–317.

    Article  CAS  PubMed  Google Scholar 

  52. Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 2010; 59: 2781–2789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008; 57: 1246–1253.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. Giralt M, Villarroya F . White, brown, beige/brite: different adipose cells for different functions? Endocrinology 2013; 154: 2992–3000.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by MINECO (grant SAF2011-23636), EU (FP7 project BETABAT, grant HEALTH-F2-2011-277713) and Generalitat de Catalunya (2009SGR-284).

Disclaimer

This article is published as part of a supplement sponsored by the Université Laval’s Research Chair in Obesity, in an effort to inform the public on the causes, consequences, treatments and prevention of obesity.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F Villarroya.

Ethics declarations

Competing interests

FV has received lecture fees from Lilly. The remaining authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cereijo, R., Villarroya, J. & Villarroya, F. Non-sympathetic control of brown adipose tissue. Int J Obes Supp 5 (Suppl 1), S40–S44 (2015). https://doi.org/10.1038/ijosup.2015.10

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijosup.2015.10

This article is cited by

Search

Quick links