Stimulation of the ß₃-Adrenergic Receptor via Mirabegron Induces Lipolysis and Thermogenesis in Human Adipocytes

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 β_1/2/3-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.