Activation of human brown adipose tissue by a β3-adrenergic receptor agonist

doi:10.1016/j.cmet.2014.12.009

Clinical Trial

. 2015 Jan 6;21(1):33-8.

doi: 10.1016/j.cmet.2014.12.009.

Activation of human brown adipose tissue by a β3-adrenergic receptor agonist

Affiliations

¹ Section of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: Aaron.Cypess@joslin.harvard.edu.
² Section of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
³ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁴ Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁵ Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, MA 02138, USA.
⁶ Section of Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.

PMID: 25565203
PMCID: PMC4298351
DOI: 10.1016/j.cmet.2014.12.009

Clinical Trial

Activation of human brown adipose tissue by a β3-adrenergic receptor agonist

Aaron M Cypess et al. Cell Metab. 2015.

. 2015 Jan 6;21(1):33-8.

doi: 10.1016/j.cmet.2014.12.009.

Affiliations

¹ Section of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: Aaron.Cypess@joslin.harvard.edu.
² Section of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
³ Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁴ Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁵ Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, MA 02138, USA.
⁶ Section of Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.

PMID: 25565203
PMCID: PMC4298351
DOI: 10.1016/j.cmet.2014.12.009

Abstract

Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of β3-adrenergic receptor (AR) agonists stimulates rodent BAT, but this activity has never been demonstrated in humans. Here we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a β3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via (18)F-fluorodeoxyglucose ((18)F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 ± 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a β3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease.

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Figures

**Figure 1. Metabolic Effects of the β3-AR Agonist Mirabegron**
(A) PET images of a 21-year-old man who was given placebo (left) or 200 mg of the β3-AR agonist mirabegron (right). Twelve male subjects were given placebo or 200 mg mirabegron. (B) BAT metabolic activity as reflected by ¹⁸F-FDG uptake. (C) Resting metabolic rate. (D) Heart rate. (E) Systolic BP. (F) Diastolic BP. Each circle represents a single subject, and the numbers correspond to subject identification number in Figure S2. The dashes represent the mean. See also Figure S2.

**Figure 2. Tissue Glucose Uptake**
¹⁸F-FDG uptake in the twelve volunteers when given placebo or 200 mg mirabegron is shown for different tissues. Each circle represents a single subject. (A) Myocardium. (B) Subcutaneous WAT. (C) Skeletal muscle. (D) Liver. See also Table S1.

**Figure 3. Predictors of Resting Metabolic Rate**
(A) Placebo-induced BAT activity. (B) Two-hundred milligram mirabegron-induced BAT activity. (C) Body fat mass with placebo. (D) Body fat mass with 200 mg mirabegron. See also Figure S3.

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References

1. Arch JR. Challenges in β(3)-Adrenoceptor Agonist Drug Development. Ther Adv Endocrinol Metab. 2011;2:59–64. - PMC - PubMed
1. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–205. - PubMed
1. Carey AL, Formosa MF, Van Every B, Bertovic D, Eikelis N, Lambert GW, Kalff V, Duffy SJ, Cherk MH, Kingwell BA. Ephedrine activates brown adipose tissue in lean but not obese humans. Diabetologia. 2013;56:147–155. - PubMed
1. Cawthorne MA, Sennitt MV, Arch JR, Smith SA. BRL 35135, a potent and selective atypical beta-adrenoceptor agonist. Am J Clin Nutr. 1992;55(Suppl):252S–257S. - PubMed
1. Chapple CR, Dvorak V, Radziszewski P, Van Kerrebroeck P, Wyndaele JJ, Bosman B, Boerrigter P, Drogendijk T, Ridder A, Van Der Putten-Slob I, Yamaguchi O Dragon Investigator Group. A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. 2013;24:1447–1458. - PMC - PubMed

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[1] Arch JR. Challenges in β(3)-Adrenoceptor Agonist Drug Development. Ther Adv Endocrinol Metab. 2011;2:59–64. - PMC - PubMed

[2] Arch JR. Challenges in β(3)-Adrenoceptor Agonist Drug Development. Ther Adv Endocrinol Metab. 2011;2:59–64. - PMC - PubMed

[3] Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–205. - PubMed

[4] Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–205. - PubMed

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

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

[7] Cawthorne MA, Sennitt MV, Arch JR, Smith SA. BRL 35135, a potent and selective atypical beta-adrenoceptor agonist. Am J Clin Nutr. 1992;55(Suppl):252S–257S. - PubMed

[8] Cawthorne MA, Sennitt MV, Arch JR, Smith SA. BRL 35135, a potent and selective atypical beta-adrenoceptor agonist. Am J Clin Nutr. 1992;55(Suppl):252S–257S. - PubMed

[9] Chapple CR, Dvorak V, Radziszewski P, Van Kerrebroeck P, Wyndaele JJ, Bosman B, Boerrigter P, Drogendijk T, Ridder A, Van Der Putten-Slob I, Yamaguchi O Dragon Investigator Group. A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. 2013;24:1447–1458. - PMC - PubMed

[10] Chapple CR, Dvorak V, Radziszewski P, Van Kerrebroeck P, Wyndaele JJ, Bosman B, Boerrigter P, Drogendijk T, Ridder A, Van Der Putten-Slob I, Yamaguchi O Dragon Investigator Group. A phase II dose-ranging study of mirabegron in patients with overactive bladder. Int Urogynecol J. 2013;24:1447–1458. - PMC - PubMed

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Activation of human brown adipose tissue by a β3-adrenergic receptor agonist

Affiliations

Activation of human brown adipose tissue by a β3-adrenergic receptor agonist

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