In rodent models, the β3-adrenergic receptor (AR) is responsible for thermogenesis in brown adipose tissue (BAT) and lipolysis in white adipose tissue (WAT). In contrast, the contribution of β3-AR in human adipocytes is controversial due to the low expression of the β3-AR in WAT and access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a selective human β3-AR agonist. In a recent clinical trial, mirabegron activated human BAT thermogenesis and WAT lipolysis. Therefore, we investigated the distribution and relative contribution of β1/2/3-AR in (i) whole white (hWAT) and brown (hBAT) adipose tissue from human autopsies and (ii) immortalized human white (hWA) and brown (hBA) adipocytes. Among the three β-ARs, β1-AR and β2-AR are similarly expressed in brown and white adipose tissue, whereas β3-AR has the highest expression in hBAT. In immortalized differentiated cells, hBA have a significantly higher expression of β3-AR compared to hWA. To assess the functionally of these receptors in adipocytes, dose-response curves of agonist-stimulated lipolysis were investigated in differentiated human and mouse adipocytes. We observed that stimulation of any one of the three β-ARs in human adipocytes induces a significant increase in glycerol release, a lipolytic byproduct. However, the effective dose of mirabegron to activate β3-AR-mediated lipolysis in white and brown adipocytes via mirabegron was significantly lower (hWA: EC50 2.55E-09; hBA: EC50 6.31E-09) compared to specific activators of β1-AR or β2-AR.

In summary, we identify a major role played by the β3-AR in the regulation of human BAT thermogenesis and WAT lipolysis, both in vivo and in vitro. Due to the comparatively minimal effects of mirabegron treatment on the cardiovascular system, selective β3-AR agonists may be the optimal choice for targeted stimulation of human WAT and BAT.


C. Cero: None. A. O'Mara: None. J.W. Johnson: None. A.S. Baskin: None. J.D. Linderman: None. A. Cypess: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at