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Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a b3-Adrenergic Receptor Agonist

Lynes et al., 2018, Cell Reports 24, 781–790

Authors: Alison S. Baskin, Joyce D. Linderman, Robert J. Brychta, Suzanne McGehee, Esti Anflick-Chames,
Cheryl Cero, James W. Johnson, Alana E. O’Mara, Laura A. Fletcher, Brooks P. Leitner,
Courtney J. Duckworth, Shan Huang, Hongyi Cai, H. Martin Garraffo, Corina M. Millo,
William Dieckmann, Vladimir Tolstikov, Emily Y. Chen, Fei Gao, Niven R. Narain, Michael A. Kiebish,
Peter J. Walter, Peter Herscovitch, Kong Y. Chen, and Aaron M. Cypess

b3-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 b3-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 onetime randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the b3-AR agonist mirabegron. There was a more–than–dose proportional increase in BAT metabolic activity as measured by [18F]-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 [SUVmean] $ 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 b3-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 b3-AR agonists to treat obesity-related complications.

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