The physiological role of the β3-AR in human adipocytes remains controversial due to its reported low expression in white adipose tissue (WAT) and previous access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a highly-selective human β3-AR agonist. In clinical trials, mirabegron treatment led to activation of human brown adipose tissue BAT thermogenesis and increased plasma non-esterified fatty acids (NEFA’s).


Therefore, we investigated whether mirabegron directly mediates lipolysis in human primary white adipocytes.


After establishing the presence of β3-AR in differentiated primary white adipocytes, we examined the functional consequences and mechanism involved by mirabegron acting on the β3-AR.Compared to β1-AR and β2-AR agonists, mirabegron potently increased intracellular glycerol release, a byproduct of lipolysis, only at low concentrations in the pico-nanomolar range. Mechanistically, at the same doses, mirabegron synergistically activated the cAMP/Protein Kinase A (cAMP/PKA) and the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) by rapidly phosphorylating hormone sensitive lipase (pHSL), cAMP response element binding (pCREB), and ERK1/2. Importantly, when either the PKA or ERK pathway was inhibited, mirabegron induced lipolysis by potentiating the complementary pathway.


In summary, we identified a major role played by the β3-AR in the regulation of human WAT lipolysis. Mirabegron acts as a potent pro-lipolytic effector, signaling through the simultaneous recruitment of two distinct signaling cascades.Therefore, activating WAT lipolysis via the β3-AR is a promising approach to increase fatty acid oxidation and fuel brown adipose tissue thermogenesis.