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Activating Human Adipose Tissue with the β3-Adrenergic Agonist Mirabegron

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Brown Adipose Tissue

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2448))

Abstract

An appealing strategy for treatment of metabolic disease in humans is activation of brown adipose tissue (BAT), a thermogenic organ best visualized through 18F-FDG PET/CT. BAT has been activated to varying degrees by mild cold exposure. However, this approach can cause undesirable stress, and there remains no consensus protocol. Here, we describe standardized methods for both acute and chronic activation of BAT using the orally administered β3-adrenergic receptor (AR) agonist, mirabegron. Acute pharmacological stimulation has enabled quantification of whole-body BAT volume and metabolic activity using PET/CT imaging, and chronic stimulation increases these properties of BAT over time.

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References

  1. Moonen MPB, Nascimento EBM, van Marken Lichtenbelt WD (2019) Human brown adipose tissue: underestimated target in metabolic disease? Biochim Biophys Acta Mol Cell Biol Lipids 1864:104–112

    Article  CAS  PubMed  Google Scholar 

  2. 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 360:1500–1508

    Article  PubMed  Google Scholar 

  3. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525

    Article  CAS  PubMed  Google Scholar 

  4. Blondin DP, Labbe SM, Tingelstad HC, Noll C, Kunach M, Phoenix S, Guerin 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:E438–E446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen KY, Brychta RJ, Linderman JD, Smith S, Courville A, Dieckmann W, Herscovitch P, Millo CM, Remaley A, Lee P, Celi FS (2013) Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J Clin Endocrinol Metab 98:E1218–E1223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hanssen MJ, Hoeks J, Brans B, van der Lans AA, Schaart G, van den Driessche JJ, Jorgensen 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 21:863–865

    Article  CAS  PubMed  Google Scholar 

  7. van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jorgensen 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 123:3395–3403

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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 123:3404–3408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cypess AM, Haft CR, Laughlin MR, Hu HH (2014) Brown fat in humans: consensus points and experimental guidelines. Cell Metab 20:408–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen KY, Cypess AM, Laughlin MR, Haft CR, Hu HH, Bredella MA, Enerback S, Kinahan PE, Lichtenbelt W, Lin FI, Sunderland JJ, Virtanen KA, Wahl RL (2016) Brown adipose reporting criteria in imaging STudies (BARCIST 1.0): recommendations for standardized FDG-PET/CT experiments in humans. Cell Metab 24:210–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Carey AL, Formosa MF, Van Every B, Bertovic D, Eikelis N, Lambert GW, Kalff V, Duffy SJ, Cherk MH, Kingwell BA (2013) Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia 56:147–155

    Article  CAS  PubMed  Google Scholar 

  12. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elia E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM (2015) Activation of human brown adipose tissue by a beta3-adrenergic receptor agonist. Cell Metab 21:33–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Broeders EP, Nascimento EB, Havekes B, Brans B, Roumans KH, Tailleux A, Schaart G, Kouach M, Charton J, Deprez B, Bouvy ND, Mottaghy F, Staels B, van Marken Lichtenbelt WD, Schrauwen P (2015) The bile acid chenodeoxycholic acid increases human Brown adipose tissue activity. Cell Metab 22:418–426

    Article  CAS  PubMed  Google Scholar 

  14. Li Y, Schnabl K, Gabler SM, Willershauser M, Reber J, Karlas A, Laurila S, Lahesmaa M, Din MU, Bast-Habersbrunner A, Virtanen KA, Fromme T, Bolze F, O’Farrell LS, Alsina-Fernandez J, Coskun T, Ntziachristos V, Nuutila P, Klingenspor M (2018) Secretin-activated Brown fat mediates prandial thermogenesis to induce satiation. Cell 175:1561–1574.e1512

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Arch JR (2008) The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from beta3-adrenoceptor agonists. Naunyn Schmiedeberg’s Arch Pharmacol 378:225–240

    Article  CAS  Google Scholar 

  17. Arch JR (2011) Challenges in beta(3)-adrenoceptor agonist drug development. Ther Adv Endocrinol Metab 2:59–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 beta3-adrenergic receptor agonist. Diabetes 67:2113–2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, Jespersen NZ, Kooijman S, Boon MR, Fortin M, Phoenix S, Frisch F, Guerin B, Turcotte EE, Haman F, Richard D, Picard F, Rensen PCN, Scheele C, Carpentier AC (2020) Human Brown adipocyte thermogenesis is driven by beta2-AR stimulation. Cell Metab 32:287–300.e287

    Article  CAS  PubMed  Google Scholar 

  20. 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:e121510

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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 130:2209–2219

    Article  PubMed  PubMed Central  Google Scholar 

  22. 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 beta3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J Clin Invest 130:2319–2331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerback S, Virtanen KA (2011) Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 14:272–279

    Article  CAS  PubMed  Google Scholar 

  24. Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin 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 122:545–552

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kushchayeva YS, Startzell M, Cochran E, Auh S, Sekizkardes H, Soldin SJ, Kushchayev SV, Dieckmann W, Skarulis M, Abdul Sater Z, Brychta RJ, Cypess AM, Lin TC, Lightbourne M, Millo C, Brown RJ (2020) Thyroid hormone effects on glucose disposal in patients with insulin receptor mutations. J Clin Endocrinol Metab 105:e158–e171

    Article  PubMed  Google Scholar 

  26. Chen KY, Smith S, Ravussin E, Krakoff J, Plasqui G, Tanaka S, Murgatroyd P, Brychta R, Bock C, Carnero E, Schoffelen P, Hatamoto Y, Rynders C, Melanson EL (2020) Room indirect calorimetry operating and reporting standards (RICORS 1.0): a guide to conducting and reporting human whole-room calorimeter studies. Obesity (Silver Spring) 28:1613–1625

    Article  PubMed  Google Scholar 

  27. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Barbaras L, Tal I, Palmer MR, Parker JA, Kolodny GM (2007) Shareware program for nuclear medicine and PET/CT PACS display and processing. AJR Am J Roentgenol 188:W565–W568

    Article  PubMed  Google Scholar 

  29. 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 114:8649–8654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 43:633–637

    Article  CAS  Google Scholar 

  31. 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 92:696–706

    Article  CAS  PubMed  Google Scholar 

  32. 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 360:1509–1517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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 58:1526–1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Senn JR, Maushart CI, Gashi G, Michel R, Lalive d’Epinay M, Vogt R, Becker AS, Muller J, Balaz M, Wolfrum C, Burger IA, Betz MJ (2018) Outdoor temperature influences cold induced thermogenesis in humans. Front Physiol 9:1184

    Article  PubMed  PubMed Central  Google Scholar 

  35. Becher T, Palanisamy S, Kramer DJ, Eljalby M, Marx SJ, Wibmer AG, Butler SD, Jiang CS, Vaughan R, Schoder H, Mark A, Cohen P (2021) Brown adipose tissue is associated with cardiometabolic health. Nat Med 27:58–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 321:642–647

    Article  CAS  PubMed  Google Scholar 

  37. Martinez-Tellez B, Nahon KJ, Sanchez-Delgado G, Abreu-Vieira G, Llamas-Elvira JM, van Velden FHP, Pereira Arias-Bouda LM, Rensen PCN, Boon MR, Ruiz JR (2018) The impact of using BARCIST 1.0 criteria on quantification of BAT volume and activity in three independent cohorts of adults. Sci Rep 8:8567

    Article  PubMed  PubMed Central  Google Scholar 

  38. Crandall JP, Gajwani P, O H J, Mawhinney DD, Sterzer F, Wahl RL (2019) Repeatability of brown adipose tissue measurements on FDG PET/CT following a simple cooling procedure for BAT activation. PLoS One 14:e0214765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nazeri A, Crandall JP, Fraum TJ, Wahl RL (2020) Repeatability of radiomic features of Brown adipose tissue. J Nucl Med, jnumed.120.2486

    Google Scholar 

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Acknowledgments

This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), DK071013, DK071014, DK075112, DK075115, and DK075116.

Author Contributions

KYC, RJB, NSI, AJ, HJL, TNL, AEP, AMC all wrote sections and contributed to the editing of the manuscript.

Author information

Authors and Affiliations

  1. Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes, Bethesda, MD, USA

    Kong Y. Chen, Robert J. Brychta, Nikita S. Israni, Alex Jiang, Hannah J. Lea, Taylor N. Lentz, Anne E. Pierce & Aaron M. Cypess

  2. Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Kong Y. Chen, Robert J. Brychta, Nikita S. Israni, Alex Jiang, Hannah J. Lea, Taylor N. Lentz, Anne E. Pierce & Aaron M. Cypess

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  1. Kong Y. Chen
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  2. Robert J. Brychta
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  3. Nikita S. Israni
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  4. Alex Jiang
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  5. Hannah J. Lea
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  6. Taylor N. Lentz
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  8. Aaron M. Cypess
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Corresponding authors

Correspondence to Kong Y. Chen or Aaron M. Cypess .

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Editors and Affiliations

  1. Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA, USA

    David A. Guertin

  2. ETH Zürich, Schwerzenbach, Zürich, Switzerland

    Christian Wolfrum

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Chen, K.Y. et al. (2022). Activating Human Adipose Tissue with the β3-Adrenergic Agonist Mirabegron. In: Guertin, D.A., Wolfrum, C. (eds) Brown Adipose Tissue. Methods in Molecular Biology, vol 2448. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2087-8_5

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  • DOI: https://doi.org/10.1007/978-1-0716-2087-8_5

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2086-1

  • Online ISBN: 978-1-0716-2087-8

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