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Baskin, Alison S; Linderman, Joyce D; Brychta, Robert J; McGehee, Suzanne; Anflick-Chames, Esti; Cero, Cheryl; Johnson, James W; O'Mara, Alana E; Fletcher, Laura A; Leitner, Brooks P; Duckworth, Courtney J; Huang, Shan; Cai, Hongyi; Garraffo, H Martin; Millo, Corina M; Dieckmann, William; Tolstikov, Vladimir; Chen, Emily Y; Gao, Fei; Narain, Niven R; Kiebish, Michael A; Walter, Peter J; Herscovitch, Peter; Chen, Kong Y; Cypess, Aaron M
Diabetes (New York, N.Y.), 10/2018, Letnik: 67, Številka: 10Journal Article
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 twelve 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-FDG PET/CT (medians 0.0 vs. 18.2 vs. 305.6 mL*SUVmean*g/mL). Only the 200 mg dose elevated both non-esterified 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 WAT 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.
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in: SICRIS
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