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

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


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: NCT01950520.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetanilides / pharmacology*
  • Adipose Tissue, Brown / metabolism
  • Adolescent
  • Adrenergic beta-Agonists / pharmacology*
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Bile Acids and Salts / metabolism*
  • Gallbladder / drug effects*
  • Gallbladder / metabolism*
  • Healthy Volunteers
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • RNA, Messenger / genetics
  • Receptors, Adrenergic, beta / genetics
  • Receptors, Adrenergic, beta / metabolism*
  • Receptors, Adrenergic, beta-3 / genetics
  • Receptors, Adrenergic, beta-3 / metabolism
  • Thermogenesis / drug effects
  • Thermogenesis / genetics
  • Thiazoles / pharmacology*
  • Young Adult


  • Acetanilides
  • Adrenergic beta-Agonists
  • Bile Acids and Salts
  • RNA, Messenger
  • Receptors, Adrenergic, beta
  • Receptors, Adrenergic, beta-3
  • Thiazoles
  • mirabegron

Associated data