ESPEYB17 11. Obesity and Weight Regulation Body Weight Regulation and Insulin Sensitivity (4 abstracts)
11.9. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity
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
Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA, aaron.cypess@nih.gov
To read the full abstract: J Clin Invest. 2020;130(5):2209–2219. doi: https://pubmed.ncbi.nlm.nih.gov/31961826/
This clinical study addressed the chronic effects of the β3-adrenergic receptor agonist mirabegron on BAT activity, blood parameters, and insulin sensitivity in a small cohort of healthy women (n =14). Participants were treated for 4 weeks orally with mirabegron 100 mg per day. BAT activity was assessed by 18F-FDG PET/CT at baseline and after the treatment period. Additionally, resting energy expenditure (REE), plasma metabolites, as well as glucose and insulin metabolism were investigated.
Attempts to treat obesity by behavioral interventions alone have been largely unsuccessful, thus complementary pharmacological treatment might be necessary to improve outcomes. In rodent models, targeting β3-adrenergic receptors seemed to be an attractive target as agonists improved energy expenditure and glucose homeostasis (1). However, in humans, limited bioavailability and cardiovascular side effects hampered consideration of β3 agonists a useful therapy (2). Recently, mirabegron, a β3 agonist used to treat overactive bladder, was reported to improve glucose homeostasis and insulin sensitivity in mice (3), by inducing brown adipose tissue (BAT) activity.
In accordance with previous evidence for acute effects of mirabegron in male subjects (4), here, chronic mirabegron treatment increased BAT activity and REE, but had no effect on body weight or body composition. Additionally, treatment improved insulin sensitivity and glucose tolerance as well as insulin secretion. These data demonstrate that chronic mirabegron treatment can activate BAT and may be useful to improve glucose metabolism. However, it still must be addressed whether the improved glucose homeostasis is a direct result of BAT activation. One interesting aspect could be the increase in plasma bile acid levels seen in this study and a previous one (5). Bile acids have been demonstrated to have multiple beneficial effects on metabolism via the liver, intestine, BAT, and microbiome. Further studies might address whether bile acids contribute to the metabolic effects of chronic β3-adrenergic treatment.
References:
1. Liu X, Pérusse F, Bukowiecki LJ. Mechanisms of the antidiabetic effects of the β3-adrenergic agonist CL-316243 in obese Zucker-ZDF rats. Am J Physiol – Regul Integr Comp Physiol 1998;274 (5):43–5. doi: 10.1152\ajpregu. 1998.274. 5r1212.
2. Arch JRS. Challenges in 3-adrenoceptor agonist drug development. Ther Adv Endocrinol Metab 2011;2 (2):59–64. doi: 10.1177/2042018811398517.
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):419–27. doi: 10.1124/jpet.118. 255778.
4. 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. 2014.12.009.6. 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. Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by A b3-adrenergic receptor agonist. Diabetes 2018;67 (10):2113–25. doi: 10.2337/db18-0462.
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