Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a β3-Adrenergic Receptor Agonist

Abstract

β3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human β3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the β3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ⋅ mean standardized uptake value [SUV] ⋅ g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human β3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective β3-AR agonists to treat obesity-related complications.

Acute metabolic and cardiovascular effects of mirabegron in healthy individuals

“…Conversely, because a 200‐mg dose is known to increase BAT activity measured via [ 18 F]‐FDG PET/CT, all doses within the range of 50 to 200 mg are likely to have efficacy in this regard. This has been supported by a recent study examining single 50‐ and 200‐mg doses of mirabegron administered to 12 healthy individuals . A dose‐dependent response with BAT activity was evident, with half the participants showing either no change or a negligible increase after the 50‐mg dose, and only one non‐responder to the 200‐mg dose.…”

“…A dose‐dependent response with BAT activity was evident, with half the participants showing either no change or a negligible increase after the 50‐mg dose, and only one non‐responder to the 200‐mg dose. These new data, combined with the present study, suggest further studies are required to determine BAT activity responses for mirabegron doses between 50 and 200 mg.…”

Multi-OMIC analysis of brain and serum from chronically-stressed mice reveals network disruptions in purine metabolism, fatty acid beta-oxidation, and antioxidant activity that are reversed by antidepressant treatment

“…Metabolomic analyses were performed using untargeted and targeted protocols as described previously [8][9][10][11] . Metabolite extraction was achieved using a mixture of isopropanol:acetonitrile:water (3:3:2 v/v/v).…”

Beta-3 Adrenoreceptors protect from hypertrophic remodelling through AMP-Activated Protein Kinase and Autophagy

“…Given the ubiquitous expression and widespread role of AMPK, it would be of interest to verify similar coupling to β3-AR in other tissues. β3-AR transcripts 30 and proteins 31 have clearly been identified in human white and brown adipocytes, where they can be activated by selective β3-AR agonists, such as mirabegron 30 . Given the emerging importance of brown adipose tissue in regulating metabolism and cardiovascular function 32,33 , and the role of AMPK in promoting mitochondrial biogenesis 34 , critical for brown fat lipolytic activity, we can speculate that the β3-AR coupling mechanism identified here could be exploited therapeutically to prevent or treat cardiovascular diseases associated with obesity and disordered metabolism.…”