Skip to main content

Advertisement

SpringerLink
Log in

The involvement of the adrenergic nervous system in activating human brown adipose tissue and browning

  • Review Article
  • Published:
Hormones Aims and scope Submit manuscript

Abstract

Obesity is a chronic condition of multifactorial etiology characterized by excessive body fat due to a calorie intake higher than energy expenditure. Given the intrinsic limitations of surgical interventions and the difficulties associated with lifestyle changes, pharmacological manipulation is currently one of the main therapies for metabolic diseases. Approaches aiming to promote energy expenditure through induction of thermogenesis have been explored and, in this context, brown adipose tissue (BAT) activation and browning have been shown to be promising strategies. Although such processes are physiologically stimulated by the sympathetic nervous system, not all situations that are known to increase adrenergic signaling promote a concomitant increase in BAT activation or browning in humans. Thus, a better understanding of factors involved in the thermogenesis attributed to these tissues is needed to enable the development of future therapies against obesity. Herein we carry out a critical review of original articles in humans under conditions previously known to trigger adrenergic responses—namely, cold, catecholamine-secreting tumor (pheochromocytoma and paraganglioma), burn injury, and adrenergic agonists—and discuss which of them are associated with increased BAT activation and browning. BAT is clearly stimulated in individuals exposed to cold or treated with high doses of the β3-adrenergic agonist mirabegron, whereas browning is certainly induced in patients after burn injury or with pheochromocytoma, as well as in individuals treated with β3-adrenergic agonist mirabegron for at least 10 weeks. Given the potential effect of increasing energy expenditure, adrenergic stimuli are promising strategies in the treatment of metabolic diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Arterburn DE, Courcoulas AP (2014) Bariatric surgery for obesity and metabolic conditions in adults. BMJ 349:g3961. https://doi.org/10.1136/bmj.g3961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS, McGehee S, Tal I, Dieckmann W, Gupta G, Kolodny GM, Pacak K, Herscovitch P, Cypess AM, Chen KY (2017) Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci U S A 114(32):8649–8654. https://doi.org/10.1073/pnas.1705287114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen KY, Brychta RJ, Abdul Sater Z, Cassimatis TM, Cero C, Fletcher LA, Israni NS, Johnson JW, Lea HJ, Linderman JD, O’Mara AE, Zhu KY, Cypess AM (2020) Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity. J Biol Chem 295(7):1926–1942. https://doi.org/10.1074/jbc.REV119.007363

    Article  CAS  PubMed  Google Scholar 

  4. Fernández-Verdejo R, Marlatt KL, Ravussin E, Galgani JE (2019) Contribution of brown adipose tissue to human energy metabolism. Mol Aspects Med 68:82–89. https://doi.org/10.1016/j.mam.2019.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Marlatt KL, Chen KY, Ravussin E (2018) Is activation of human brown adipose tissue a viable target for weight management? Am J Physiol Regul Integr Comp Physiol 315(3):R479–R483. https://doi.org/10.1152/ajpregu.00443.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T, Kawai Y, Miyagawa M, Tsujisaki M, Saito M (2011) Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity (Silver Spring) 19(9):1755–1760. https://doi.org/10.1038/oby.2011.125

    Article  Google Scholar 

  7. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M (2013) Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 123(8):3404–3408. https://doi.org/10.1172/JCI67803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ravussin E, Galgani JE (2011) The implication of brown adipose tissue for humans. Annu Rev Nutr 31:33–47. https://doi.org/10.1146/annurev-nutr-072610-145209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bhatt PS, Dhillo WS, Salem V (2017) Human brown adipose tissue-function and therapeutic potential in metabolic disease. Curr Opin Pharmacol 37:1–9. https://doi.org/10.1016/j.coph.2017.07.004

    Article  CAS  PubMed  Google Scholar 

  10. Bachman ES, Dhillon H, Zhang CY, Cinti S, Bianco AC, Kobilka BK, Lowell BB (2002) β-AR signaling required for diet-induced thermogenesis and obesity resistance. Science 297(5582):843–845. https://doi.org/10.1126/science.1073160

    Article  CAS  PubMed  Google Scholar 

  11. Asensio C, Jimenez M, Kühne F, Rohner-Jeanrenaud F, Muzzin P (2005) The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes 54(12):3490–3495. https://doi.org/10.2337/diabetes.54.12.3490

    Article  CAS  PubMed  Google Scholar 

  12. De Jong JMA, Sun W, Pires ND, Frontini A, Balaz M, Jespersen NZ, Feizi A, Petrovic K, Fischer AW, Bokhari MH, Niemi T, Nuutila P, Cinti S, Nielsen S, Scheele C, Virtanen K, Cannon B, Nedergaard J, Wolfrum C, Petrovic N (2019) Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nat Metab 1(8):830–843. https://doi.org/10.1038/s42255-019-0101-4

    Article  PubMed  Google Scholar 

  13. Van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360(15):1500–1508. https://doi.org/10.1056/NEJMoa0808718

    Article  PubMed  Google Scholar 

  14. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360(15):1518–1525. https://doi.org/10.1056/NEJMoa0808949

    Article  CAS  PubMed  Google Scholar 

  15. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58(7):1526–1531. https://doi.org/10.2337/db09-0530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, Saito M (2011) Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring) 19(1):13–16. https://doi.org/10.1038/oby.2010.105

    Article  Google Scholar 

  17. Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerbäck S, Virtanen KA (2011) Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 14(2):272–279. https://doi.org/10.1016/j.cmet.2011.06.012

    Article  CAS  PubMed  Google Scholar 

  18. Iwen KA, Backhaus J, Cassens M, Waltl M, Hedesan OC, Merkel M, Heeren J, Sina C, Rademacher L, Windjäger A, Haug AR, Kiefer FW, Lehnert H, Schmid SM (2017) Cold-induced brown adipose tissue activity alters plasma fatty acids and improves glucose metabolism in men. J Clin Endocrinol Metab 102(11):4226–4234. https://doi.org/10.1210/jc.2017-01250

    Article  PubMed  Google Scholar 

  19. Martinez-Tellez B, Xu H, Sanchez-Delgado G, Acosta FM, Rensen PCN, Llamas-Elvira JM, Ruiz JR (2018) Association of wrist and ambient temperature with cold-induced brown adipose tissue and skeletal muscle [18F]FDG uptake in young adults. Am J Physiol Regul Integr Comp Physiol 315(6):R1281–R1288. https://doi.org/10.1152/ajpregu.00238.2018

    Article  CAS  PubMed  Google Scholar 

  20. Oreskovich SM, Ong FJ, Ahmed BA, Konyer NB, Blondin DP, Gunn E, Singh NP, Noseworthy MD, Haman F, Carpentier AC, Punthakee Z, Steinberg GR, Morrison KM (2019) MRI reveals human brown adipose tissue is rapidly activated in response to cold. J Endocr Soc 3(12):2374–2384. https://doi.org/10.1210/js.2019-00309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Leitner BP, Weiner LS, Desir M, Kahn PA, Selen DJ, Tsang C, Kolodny GM, Cypess AM (2019) Kinetics of human brown adipose tissue activation and deactivation. Int J Obes (Lond) 43(3):633–637. https://doi.org/10.1038/s41366-018-0104-3

    Article  CAS  Google Scholar 

  22. Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F, Turcotte EE, Richard D, Carpentier AC (2012) Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 122(2):545–552. https://doi.org/10.1172/JCI60433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chondronikola M, Volpi E, Børsheim E, Porter C, Saraf MK, Annamalai P, Yfanti C, Chao T, Wong D, Shinoda K, Labbė SM, Hurren NM, Cesani F, Kajimura S, Sidossis LS (2016) Brown adipose tissue activation is linked to distinct systemic effects on lipid metabolism in humans. Cell Metab 23(6):1200–1206. https://doi.org/10.1016/j.cmet.2016.04.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, Van Marken Lichtenbelt WD (2011) Brown adipose tissue in morbidly obese subjects. PLoS ONE 6(2):e17247. https://doi.org/10.1371/journal.pone.0017247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517. https://doi.org/10.1056/NEJMoa0810780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee P, Smith S, Linderman J, Courville AB, Brychta RJ, Dieckmann W, Werner CD, Chen KY, Celi FS (2014) Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63(11):3686–3698. https://doi.org/10.2337/db14-0513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blondin DP, Labbé SM, Tingelstad HC, Noll C, Kunach M, Phoenix S, Guérin B, Turcotte EE, Carpentier AC, Richard D, Haman F (2014) Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J Clin Endocrinol Metab 99(3):E438-446. https://doi.org/10.1210/jc.2013-3901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hanssen MJ, Hoeks J, Brans B, van der Lans AA, Schaart G, van den Driessche JJ, Jörgensen JA, Boekschoten MV, Hesselink MK, Havekes B, Kersten S, Mottaghy FM, van Marken Lichtenbelt WD, Schrauwen P (2015) Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat Med 21(8):863–865. https://doi.org/10.1038/nm.3891

    Article  CAS  PubMed  Google Scholar 

  29. Hanssen MJ, van der Lans AA, Brans B, Hoeks J, Jardon KM, Schaart G, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD (2016) Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 65(5):1179–1189. https://doi.org/10.2337/db15-1372

    Article  CAS  PubMed  Google Scholar 

  30. Yoneshiro T, Matsushita M, Nakae S, Kameya T, Sugie H, Tanaka S, Saito M (2016) Brown adipose tissue is involved in the seasonal variation of cold-induced thermogenesis in humans. Am J Physiol Regul Integr Comp Physiol 310(10):R999–R1009. https://doi.org/10.1152/ajpregu.00057.2015

    Article  PubMed  Google Scholar 

  31. Senn JR, Maushart CI, Gashi G, Michel R, Lalive d’Epinay M, Vogt R, Becker AS, Müller J, Baláz M, Wolfrum C, Burger IA, Betz MJ (2018) Outdoor temperature influences cold induced thermogenesis in humans. Front Physiol 9:1184. https://doi.org/10.3389/fphys.2018.01184

    Article  PubMed  PubMed Central  Google Scholar 

  32. Muzik O, Mangner TJ, Leonard WR, Kumar A, Janisse J, Granneman JG (2013) 15O PET measurement of blood flow and oxygen consumption in cold-activated human brown fat. J Nucl Med 54(4):523–531. https://doi.org/10.2967/jnumed.112.111336

    Article  CAS  PubMed  Google Scholar 

  33. Blondin DP, Labbé SM, Phoenix S, Guérin B, Turcotte É, Richard D, Carpentier AC, Haman F (2015) Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men. J Physiol 593(3):701–714. https://doi.org/10.1113/jphysiol.2014.283598

    Article  CAS  PubMed  Google Scholar 

  34. Kern PA, Finlin BS, Zhu B, Rasouli N, McGehee RE, Westgate PM, Dupont-Versteegden EE (2014) The effects of temperature and seasons on subcutaneous white adipose tissue in humans: evidence for thermogenic gene induction. J Clin Endocrinol Metab 99(12):E2772-2779. https://doi.org/10.1210/jc.2014-2440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Finlin BS, Memetimin H, Confides AL, Kasza I, Zhu B, Vekaria HJ, Harfmann B, Jones KA, Johnson ZR, Westgate PM, Alexander CM, Sullivan PG, Dupont-Versteegden EE, Kern PA (2018). Human adipose beiging in response to cold and mirabegron. JCI Insight. 3(15). https://doi.org/10.1172/jci.insight.121510

  36. Van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jörgensen JA, Wu J, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD (2013) Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest 123(8):3395–3403. https://doi.org/10.1172/JCI68993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Greaney JL, Kenney WL, Alexander LM (2016) Sympathetic regulation during thermal stress in human aging and disease. Auton Neurosci 196:81–90. https://doi.org/10.1016/j.autneu.2015.11.002

    Article  PubMed  Google Scholar 

  38. Ludwig J, Gerlich M, Halbrügge T, Graefe KH (1990) The synaptic noradrenaline concentration in humans as estimated from simultaneous measurements of plasma noradrenaline and dihydroxyphenylglycol (DOPEG). J Neural Transm Suppl 32:441–445. https://doi.org/10.1007/978-3-7091-9113-2_60

    Article  CAS  PubMed  Google Scholar 

  39. Erlic Z, Beuschlein F (2019) Metabolic alterations in patients with pheochromocytoma. Exp Clin Endocrinol Diabetes 127(2–03):129–136. https://doi.org/10.1055/a-0649-0960

    Article  CAS  PubMed  Google Scholar 

  40. Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, Lichtenberg TM, Murray BA, Ghayee HK, Else T, Ling S, Jefferys SR, de Cubas AA, Wenz B, Korpershoek E, Amelio AL, Makowski L, Rathmell WK, Gimenez-Roqueplo AP, Giordano TJ, Asa SL, Tischler AS, Pacak K, Nathanson KL, Wilkerson MD, Network CGAR (2017) Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31(2):181–193. https://doi.org/10.1016/j.ccell.2017.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Crona J, Taïeb D, Pacak K (2017) New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocr Rev 38(6):489–515. https://doi.org/10.1210/er.2017-00062

    Article  PubMed  PubMed Central  Google Scholar 

  42. Crona J, Lamarca A, Ghosal S, Welin S, Skogseid B, Pacak K (2019) Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis. Endocr Relat Cancer 26(5):539–550. https://doi.org/10.1530/ERC-19-0024

    Article  CAS  PubMed  Google Scholar 

  43. Hadi M, Chen CC, Whatley M, Pacak K, Carrasquillo JA (2007) Brown fat imaging with (18)F-6-fluorodopamine PET/CT, (18)F-FDG PET/CT, and (123)I-MIBG SPECT: a study of patients being evaluated for pheochromocytoma. J Nucl Med 48(7):1077–1083. https://doi.org/10.2967/jnumed.106.035915

    Article  CAS  PubMed  Google Scholar 

  44. Wang Q, Zhang M, Ning G, Gu W, Su T, Xu M, Li B, Wang W (2011) Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity. PLoS ONE 6(6):e21006. https://doi.org/10.1371/journal.pone.0021006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Puar T, van Berkel A, Gotthardt M, Havekes B, Hermus AR, Lenders JW, van Marken Lichtenbelt WD, Xu Y, Brans B, Timmers HJ (2016) Genotype-dependent brown adipose tissue activation in patients with pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 101(1):224–232. https://doi.org/10.1210/jc.2015-3205

    Article  CAS  PubMed  Google Scholar 

  46. Abdul Sater Z, Jha A, Hamimi A, Mandl A, Hartley IR, Gubbi S, Patel M, Gonzales M, Taïeb D, Civelek AC, Gharib AM, Auh S, O’Mara AE, Pacak K, Cypess AM (2020). Pheochromocytoma and paraganglioma patients with poor survival often show brown adipose tissue activation. J Clin Endocrinol Metab. 105(4). https://doi.org/10.1210/clinem/dgz314

  47. Frontini A, Vitali A, Perugini J, Murano I, Romiti C, Ricquier D, Guerrieri M, Cinti S (2013) White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma. Biochim Biophys Acta 1831(5):950–959. https://doi.org/10.1016/j.bbalip.2013.02.005

    Article  CAS  PubMed  Google Scholar 

  48. Betz MJ, Slawik M, Lidell ME, Osswald A, Heglind M, Nilsson D, Lichtenauer UD, Mauracher B, Mussack T, Beuschlein F, Enerbäck S (2013) Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature. J Clin Endocrinol Metab 98(10):4097–4104. https://doi.org/10.1210/jc.2012-3535

    Article  CAS  PubMed  Google Scholar 

  49. Di Franco A, Guasti D, Mazzanti B, Ercolino T, Francalanci M, Nesi G, Bani D, Forti G, Mannelli M, Valeri A, Luconi M (2014) Dissecting the origin of inducible brown fat in adult humans through a novel adipose stem cell model from adipose tissue surrounding pheochromocytoma. J Clin Endocrinol Metab 99(10):E1903-1912. https://doi.org/10.1210/jc.2014-1431

    Article  CAS  PubMed  Google Scholar 

  50. Hondares E, Gallego-Escuredo JM, Flachs P, Frontini A, Cereijo R, Goday A, Perugini J, Kopecky P, Giralt M, Cinti S, Kopecky J, Villarroya F (2014) Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue. Metabolism 63(3):312–317. https://doi.org/10.1016/j.metabol.2013.11.014

    Article  CAS  PubMed  Google Scholar 

  51. Nagano G, Ohno H, Oki K, Kobuke K, Shiwa T, Yoneda M, Kohno N (2015) Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with PRDM16-EHMT1 complex expression. PLoS ONE 10(3):e0122584. https://doi.org/10.1371/journal.pone.0122584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vergnes L, Davies GR, Lin JY, Yeh MW, Livhits MJ, Harari A, Symonds ME, Sacks HS, Reue K (2016) Adipocyte browning and higher mitochondrial function in periadrenal but not SC fat in pheochromocytoma. J Clin Endocrinol Metab 101(11):4440–4448. https://doi.org/10.1210/jc.2016-2670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Williams FN, Jeschke MG, Chinkes DL, Suman OE, Branski LK, Herndon DN (2009) Modulation of the hypermetabolic response to trauma: temperature, nutrition, and drugs. J Am Coll Surg 208(4):489–502. https://doi.org/10.1016/j.jamcollsurg.2009.01.022

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sommerhalder C, Blears E, Murton AJ, Porter C, Finnerty C, Herndon DN (2020) Current problems in burn hypermetabolism. Curr Probl Surg 57(1):100709. https://doi.org/10.1016/j.cpsurg.2019.100709

    Article  PubMed  Google Scholar 

  55. Jeschke MG, Chinkes DL, Finnerty CC, Kulp G, Suman OE, Norbury WB, Branski LK, Gauglitz GG, Mlcak RP, Herndon DN (2008) Pathophysiologic response to severe burn injury. Ann Surg 248(3):387–401. https://doi.org/10.1097/SLA.0b013e3181856241

    Article  PubMed  Google Scholar 

  56. Jeschke MG, Gauglitz GG, Kulp GA, Finnerty CC, Williams FN, Kraft R, Suman OE, Mlcak RP, Herndon DN (2011) Long-term persistance of the pathophysiologic response to severe burn injury. PLoS ONE 6(7):e212450. https://doi.org/10.1371/journal.pone.0021245

    Article  CAS  Google Scholar 

  57. Kulp GA, Herndon DN, Lee JO, Suman OE, Jeschke MG (2010) Extent and magnitude of catecholamine surge in pediatric burned patients. Shock 33(4):369–374. https://doi.org/10.1097/SHK.0b013e3181b92340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stanojcic M, Abdullahi A, Rehou S, Parousis A, Jeschke MG (2018) Pathophysiological response to burn injury in adults. Ann Surg 267(3):576–584. https://doi.org/10.1097/SLA.0000000000002097

    Article  PubMed  Google Scholar 

  59. Gauglitz GG, Herndon DN, Kulp GA, Meyer WJ, Jeschke MG (2009) Abnormal insulin sensitivity persists up to three years in pediatric patients post-burn. J Clin Endocrinol Metab 94(5):1656–1664. https://doi.org/10.1210/jc.2008-1947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wilmore DW, Aulick LH (1978) Metabolic changes in burned patients. Surg Clin North Am 58(6):1173–1187. https://doi.org/10.1016/S0039-6109(16)41685-3

    Article  CAS  PubMed  Google Scholar 

  61. Hart DW, Wolf SE, Mlcak R, Chinkes DL, Ramzy PI, Obeng MK, Ferrando AA, Wolfe RR, Herndon DN (2000) Persistence of muscle catabolism after severe burn. Surgery 128(2):312–319. https://doi.org/10.1067/msy.2000.108059

    Article  CAS  PubMed  Google Scholar 

  62. Kraft R, Herndon DN, Finnerty CC, Hiyama Y, Jeschke MG (2013) Association of postburn fatty acids and triglycerides with clinical outcome in severely burned children. J Clin Endocrinol Metab 98(1):314–321. https://doi.org/10.1210/jc.2012-2599

    Article  CAS  PubMed  Google Scholar 

  63. Sidossis LS, Porter C, Saraf MK, Børsheim E, Radhakrishnan RS, Chao T, Ali A, Chondronikola M, Mlcak R, Finnerty CC, Hawkins HK, Toliver-Kinsky T, Herndon DN (2015) Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 22(2):219–227. https://doi.org/10.1016/j.cmet.2015.06.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Patsouris D, Qi P, Abdullahi A, Stanojcic M, Chen P, Parousis A, Amini-Nik S, Jeschke MG (2015) Burn induces browning of the subcutaneous white adipose tissue in mice and humans. Cell Rep 13(8):1538–1544. https://doi.org/10.1016/j.celrep.2015.10.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Flores O, Stockton K, Roberts JA, Muller MJ, Paratz JD (2016) The efficacy and safety of adrenergic blockade after burn injury: a systematic review and meta-analysis. J Trauma Acute Care Surg 80(1):146–155. https://doi.org/10.1097/TA.0000000000000887

    Article  CAS  PubMed  Google Scholar 

  66. Lowell BB, Flier JS (1997) Brown adipose tissue, β 3-adrenergic receptors, and obesity. Annu Rev Med 48:307–316. https://doi.org/10.1146/annurev.med.48.1.307

    Article  CAS  PubMed  Google Scholar 

  67. Krief S, Lönnqvist F, Raimbault S, Baude B, Van Spronsen A, Arner P, Strosberg AD, Ricquier D, Emorine LJ (1993) Tissue distribution of beta 3-adrenergic receptor mRNA in man. J Clin Invest 91(1):344–349. https://doi.org/10.1172/JCI116191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Berkowitz DE, Nardone NA, Smiley RM, Price DT, Kreutter DK, Fremeau RT, Schwinn DA (1995) Distribution of β 3 -adrenoceptor mRNA in human tissues. Eur J Pharmacol Mol Pharmacol 289(2):223–228. https://doi.org/10.1016/0922-4106(95)90098-5

    Article  CAS  Google Scholar 

  69. Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F (2009) The β3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res 59(4):221–234. https://doi.org/10.1016/j.phrs.2009.01.002

    Article  CAS  PubMed  Google Scholar 

  70. Baskin AS, Linderman JD, Brychta RJ, McGehee S, Anflick-Chames E, Cero C, Johnson JW, O’Mara AE, Fletcher LA, Leitner BP, Duckworth CJ, Huang S, Cai H, Garraffo HM, Millo CM, Dieckmann W, Tolstikov V, Chen EY, Gao F, Narain NR, Kiebish MA, Walter PJ, Herscovitch P, Chen KY, Cypess AM (2018) Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by a β3-adrenergic receptor agonist. Diabetes 67(10):2113–2125. https://doi.org/10.2337/db18-0462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Peng XR, Gennemark P, O’Mahony G, Bartesaghi S (2015) Unlock the thermogenic potential of adipose tissue: pharmacological modulation and implications for treatment of diabetes and obesity. Front Endocrinol (Lausanne) 6:174. https://doi.org/10.3389/fendo.2015.00174

    Article  Google Scholar 

  72. Buemann B, Toubro S, Astrup A (2000) Effects of the two beta3-agonists, ZD7114 and ZD2079 on 24 hour energy expenditure and respiratory quotient in obese subjects. Int J Obes Relat Metab Disord 24(12):1553–1560. https://doi.org/10.1038/sj.ijo.0801452

    Article  CAS  PubMed  Google Scholar 

  73. Weyer C, Tataranni PA, Snitker S, Danforth E, Ravussin E (1998) Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective β3-adrenoceptor agonist in humans. Diabetes 47(10):1555–1561. https://doi.org/10.2337/diabetes.47.10.1555

    Article  CAS  PubMed  Google Scholar 

  74. Van Baak MA, Hul GB, Toubro S, Astrup A, Gottesdiener KM, DeSmet M, Saris WH (2002) Acute effect of L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure in obese men. Clin Pharmacol Ther 71(4):272–279. https://doi.org/10.1067/mcp.2002.122527

    Article  PubMed  Google Scholar 

  75. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A (2002) Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr 76(4):780–788. https://doi.org/10.1093/ajcn/76.4.780

    Article  CAS  PubMed  Google Scholar 

  76. Redman LM, de Jonge L, Fang X, Gamlin B, Recker D, Greenway FL, Smith SR, Ravussin E (2007) Lack of an effect of a novel beta3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals: a double-blind, placebo-controlled randomized study. J Clin Endocrinol Metab 92(2):527–531. https://doi.org/10.1210/jc.2006-1740

    Article  CAS  PubMed  Google Scholar 

  77. Malik M, van Gelderen EM, Lee JH, Kowalski DL, Yen M, Goldwater R, Mujais SK, Schaddelee MP, de Koning P, Kaibara A, Moy SS, Keirns JJ (2012) Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study. Clin Pharmacol Ther 92(6):696–706. https://doi.org/10.1038/clpt.2012.181

    Article  CAS  PubMed  Google Scholar 

  78. Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T, Sasamata M, Miyata K, Uchida H, Yamaguchi O (2007) Effect of (R)-2-(2-aminothiazol-4-yl)-4’-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321(2):642–647. https://doi.org/10.1124/jpet.106.115840

    Article  CAS  PubMed  Google Scholar 

  79. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM (2015) Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab 21(1):33–38. https://doi.org/10.1016/j.cmet.2014.12.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. O’Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, Fink YA, Kapuria D, Cassimatis TM, Kelsey N, Cero C, Sater ZA, Piccinini F, Baskin AS, Leitner BP, Cai H, Millo CM, Dieckmann W, Walter M, Javitt NB, Rotman Y, Walter PJ, Ader M, Bergman RN, Herscovitch P, Chen KY, Cypess AM (2020) Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Invest 130(5):2209–2219. https://doi.org/10.1172/JCI131126

    Article  PubMed  PubMed Central  Google Scholar 

  81. Finlin BS, Memetimin H, Zhu B, Confides AL, Vekaria HJ, El Khouli RH, Johnson ZR, Westgate PM, Chen J, Morris AJ, Sullivan PG, Dupont-Versteegden EE, Kern PA (2020) The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J Clin Invest 130(5):2319–2331. https://doi.org/10.1172/JCI134892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Loh RKC, Formosa MF, La Gerche A, Reutens AT, Kingwell BA, Carey AL (2019) Acute metabolic and cardiovascular effects of mirabegron in healthy individuals. Diabetes Obes Metab 21(2):276–284. https://doi.org/10.1111/dom.13516

    Article  CAS  PubMed  Google Scholar 

  83. Chapple CR, Kaplan SA, Mitcheson D, Klecka J, Cummings J, Drogendijk T, Dorrepaal C, Martin N (2013) Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 63(2):296–305. https://doi.org/10.1016/j.eururo.2012.10.048

    Article  CAS  PubMed  Google Scholar 

  84. Nitti VW, Chapple CR, Walters C, Blauwet MB, Herschorn S, Milsom I, Auerbach S, Radziszewski P (2014) Safety and tolerability of the β3 -adrenoceptor agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled analysis of three 12-week randomised Phase III trials and of a 1-year randomised Phase III trial. Int J Clin Pract 68(8):972–985. https://doi.org/10.1111/ijcp.12433

    Article  CAS  PubMed  Google Scholar 

  85. Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, Jespersen NZ, Kooijman S, Boon MR, Fortin M, Phoenix S, Frisch F, Guérin B, Turcotte É, Haman F, Richard D, Picard F, Rensen PCN, Scheele C, Carpentier AC (2020) Human brown adipocyte thermogenesis is driven by β2-AR stimulation. Cell Metab 32(2):287-300.e287. https://doi.org/10.1016/j.cmet.2020.07.005

    Article  CAS  PubMed  Google Scholar 

  86. Lee P, Day RO, Greenfield JR, Ho KK (2013) Formoterol, a highly β2-selective agonist, increases energy expenditure and fat utilisation in men. Int J Obes (Lond) 37(4):593–597. https://doi.org/10.1038/ijo.2012.90

    Article  CAS  Google Scholar 

  87. Onslev J, Jacobson G, Narkowicz C, Backer V, Kalsen A, Kreiberg M, Jessen S, Bangsbo J, Hostrup M (2017) β2-adrenergic stimulation increases energy expenditure at rest, but not during submaximal exercise in active overweight men. Eur J Appl Physiol 117(9):1907–1915. https://doi.org/10.1007/s00421-017-3679-9

    Article  CAS  PubMed  Google Scholar 

  88. Cero C, Lea HJ, Zhu KY, Shamsi F, Tseng YH, Cypess AM (2021). β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis. JCI Insight. 6(11). https://doi.org/10.1172/jci.insight.139160

  89. Cannon B, Nedergaard J (2011) Nonshivering thermogenesis and its adequate measurement in metabolic studies. J Exp Biol 214(Pt 2):242–253. https://doi.org/10.1242/jeb.050989

    Article  PubMed  Google Scholar 

  90. Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, Vencato J, De Stefani D, Silvestrin V, Rizzuto R, Bassetto F, De Caro R, Vettor R (2014) Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol 383(1–2):137–146. https://doi.org/10.1016/j.mce.2013.12.005

    Article  CAS  PubMed  Google Scholar 

  91. Ye L, Wu J, Cohen P, Kazak L, Khandekar MJ, Jedrychowski MP, Zeng X, Gygi SP, Spiegelman BM (2013) Fat cells directly sense temperature to activate thermogenesis. Proc Natl Acad Sci U S A 110(30):12480–12485. https://doi.org/10.1073/pnas.1310261110

    Article  PubMed  PubMed Central  Google Scholar 

  92. Ong FJ, Ahmed BA, Oreskovich SM, Blondin DP, Haq T, Konyer NB, Noseworthy MD, Haman F, Carpentier AC, Morrison KM, Steinberg GR (2018) Recent advances in the detection of brown adipose tissue in adult humans: a review. Clin Sci (Lond) 132(10):1039–1054. https://doi.org/10.1042/CS20170276

    Article  CAS  Google Scholar 

  93. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, Vetrivelan R, Lu GZ, Laznik-Bogoslavski D, Hasenfuss SC, Kajimura S, Gygi SP, Spiegelman BM (2015) A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163(3):643–655. https://doi.org/10.1016/j.cell.2015.09.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ikeda K, Kang Q, Yoneshiro T, Camporez JP, Maki H, Homma M, Shinoda K, Chen Y, Lu X, Maretich P, Tajima K, Ajuwon KM, Soga T, Kajimura S (2017) UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med 23(12):1454–1465. https://doi.org/10.1038/nm.4429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculdade Israelita de Ciências da Saúde Albert Einstein, Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil

    Yolanda Oliveira Pinto & Juliana Magdalon

  2. Instituto de Ciências Biomédicas, Universidade de São Paulo, Sao Paulo, SP, Brazil

    William Tadeu Lara Festuccia

Authors
  1. Yolanda Oliveira Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William Tadeu Lara Festuccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juliana Magdalon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juliana Magdalon.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pinto, Y.O., Festuccia, W.T.L. & Magdalon, J. The involvement of the adrenergic nervous system in activating human brown adipose tissue and browning. Hormones 21, 195–208 (2022). https://doi.org/10.1007/s42000-022-00361-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42000-022-00361-2

Keywords

Search

Navigation