ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Invest. 2020;130(5):2319–2331.

This clinical study assessed the effect of the β3-adrenergic agonist mirabegron on glucose homeostasis in obese individuals.

Chronic activation of β3-receptors in mice leads to the appearance of brown-like (e.g. ‘beige’) adipocytes in white adipose tissue, a process referred to as ‘browning’. Activation of brown adipose tissue (BAT) as well as browning has proved beneficial in rodent models (1), including improved glucose homeostasis. Mirabegron, a β3-receptor agonist approved for the treatment of overactive bladder, was recently reported to acutely activate BAT and increase resting energy expenditure in humans (2).

Here, the authors investigated whether treatment with mirabegron is beneficial for glucose homeostasis in adipose tissue and skeletal muscle of obese individuals. The study was performed in n =13 subjects (age 35–65, BMI>27) who received mirabegron 50 mg/day for 12 weeks. Before and after treatment, body composition (DEXA), OGTT, euglycemic clamp, and biopsies from muscle and s.c. adipose tissue was assessed. Additionally, PET/CT scans after cold exposure were performed to measure BAT activity. Overall, mirabegron treatment significantly improved glucose tolerance, insulin sensitivity and HbA1c levels. At the adipose level, mirabegron stimulated lipolysis, reduced fibrotic fiber protein expression, and increased the number of alternatively activated macrophages. In skeletal muscle, where β3-receptors are absent, triglyceride levels were reduced, and type-I fibers increased.

This study demonstrates for the first time that treatment with mirabegron in an FDA-approved dose is effective at improving glucose homeostasis in obese individuals. Probably because of the low mirabegron dosage, treatment had no cardiac side effects in contrast to previous studies using acute high doses (2). Interestingly, mirabegron also induced marked changes in skeletal muscle, which is devoid of b3-receptors, indicating that these changes are secondary to those in adipose tissue. However, mirabegron did not reduce body weight and failed to induce BAT activation as shown in studies with mice and humans (2–4) This might be a result of low BAT presence in obesity or due to the low dose of mirabegron used here. Larger studies including placebo controls might reveal if the effects mirabegron persist in the long run.

References:

1. Klepac K, Georgiadi A, Tschöp M, Herzig S. The role of brown and beige adipose tissue in glycaemic control. Molecular Aspects of Medicine 2019;68:90–100. doi: 10.1016/j.mam.2019.07.001.

2. Cypess AM, Weiner LS, Roberts-Toler C, Franquet E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM. Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist. Cell Metab 2015;21 (1):33–38. doi: 10.1016/j.cmet.2014.12.009.

3. Hao L, Scott S, Abbasi M, Zu Y, Khan SH, Yang Y, Wu D, Zhao L, Wang S. Beneficial metabolic effects of mirabegron in vitro and in high-fat diet-induced obese mice. J Pharmacol Exp Ther 2019;369 (3):419–427. doi: 10.1124/jpet.118.255778.

4. 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 H, Chen KY, Cypess AM. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Invest 2020;130 (5):2209–19. doi: 10.1172/jci131126.