Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist

Abstract

SUMMARY 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 18F-fluorodeoxyglucose (18F-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.

Nonalcoholic Fatty Liver Disease

“…Animal studies have provided some insights into these differences but how these will be translated into treatment of human disease is yet to be shown. Examples include the divergence of rat strains into those having high and low exercise tolerance with features of the metabolic syndrome developing in the latter 182 , the role -adrenergic stimulation of highly metabolic brown adipose tissue 183 , the role of serotonin in modulating metabolism 184 , and the role of peripheral cannabinoid signalling in modulating energy efficiency 185 187 . However, treatment was associated with significant pruritus in 23% in the treatment group compared with 6% in the placebo group and with a rise in total and LDL cholesterol and a decrease in HDL cholesterol in treated patients, the importance of which will be further assessed in another clinical trial.…”

Horizons in the Pharmacotherapy of Obesity

“…From 210 to 250 min after giving four times its therapeutic dose, it increased resting metabolic rate by 13% [74]. If this increase could be sustained over 24 hours, one would expect weight loss of 5 kg in the first year [75].…”

Glucagon increases energy expenditure independently of brown adipose tissue activation in humans

“…A more recent study, using newer and more highly specific 3 agonists (licensed for other conditions), however, suggests that pharmacological manipulation of BAT remains a viable option. Cypess et al [32] described significant BAT activation in response to a single dose of the selective agonist mirabegron, associated with a 200 kcal/day rise in EE, although this was not reported against the degree of measured cold-induced BAT activity in the cohort. More recently, Broeders et al [33] described the effect of bile acids on human BAT activation, reporting a small but significant rise in BAT SUV max , from 1.0 ± 0.4 to 1.6 ± 0.4, compared with 7.2 ± 5.4 in acute cold exposure.…”