Format

Send to

Choose Destination
Diabetes. 2018 Oct;67(10):2113-2125. doi: 10.2337/db18-0462. Epub 2018 Jul 6.

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

Author information

1
Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
2
Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
3
Department of Positron Emission Tomography, National Institutes of Health, Bethesda, MD.
4
BERG, Framingham, MA.
5
Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD aaron.cypess@nih.gov.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01950520.

PMID:
29980535
PMCID:
PMC6152342
DOI:
10.2337/db18-0462
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center