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Cited by 138

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

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.·2018·Diabetes
DOI 10.2337/db18-0462
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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 [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 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.

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Cited by

Metadata

Authors
Baskin, A. S., Linderman, J. D., Brychta, R. J., McGehee, S., Anflick-Chames, E., Cero, C., Johnson, J. W., O’Mara, A. E., Fletcher, L. A., Leitner, B. P., Duckworth, C. J., Huang, S., Cai, H., Garraffo, H. M., Millo, C. M., Dieckmann, W., Tolstikov, V., Chen, E. Y., Gao, F., Narain, N. R., Kiebish, M. A., Walter, P. J., Herscovitch, P., Chen, K. Y., & Cypess, A. M.
Venue
Diabetes
Publisher
American Diabetes Association
Published
2018-07-06
Volume
67
Issue
10
Pages
2113-2125
ISSN
  • 0012-1797
  • 1939-327X
DOI
10.2337/db18-0462
Cited by
138
References
13
Language
en
Licence
www.diabetesjournals.org/content/license (vor, 76 d)
Funders
NIDDK (DK-075112, DK-075116, DK-071013, DK-071014)

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