Stimulation of the B3 Adrenergic Receptors Prime Human White and Brown Adipocytes for Increased Lipolysis and Thermogenesis

Recent clinical trials show that chronic activation of the β3-adrenergic receptor (AR) by mirabegron leads to numerous beneficial physiological responses, including increased energy expenditure, insulin sensitivity, and improved lipoprotein profile. Preliminary evidence suggests that they are mediated in part through adaptations by adipose tissue, but little is known about how mirabegron affects the cellular metabolism of human white or brown adipocytes (hWA and BA, respectively). We therefore treated paired immortalized hWA and hBA for 6 hours with a range of mirabegron doses (1 nM - 10 µM), as well as the β1- and β2-AR selective agonists, dobutamine and terbutaline, at 10 µM. We found that in untreated cells, ADRB1 and ADRB2 were higher in hWA than hBA, but ADRB3 was higher in hBA. However, mirabegron at all concentrations increased the expression of ADRB3 in hWA, and the highest dose of mirabegron boosted expression above that in hBA. While an increase in ADRB3 was detected in hWA with β1- and β2-agonist treatment, no changes occurred to the other two β-ARs when exposed to their selective agonists. Downstream, the β1- and β2-agonists increased thermogenic UCP1 expression in hWA, but mirabegron raised UCP1 expression only in hBA. Among the genes associated with lipolysis, glucose metabolism, and insulin signaling, mirabegron 10 µM promoted the expression of ATGL and HSL encoding genes, as well as GLUT4 in hBA only. In contrast, no changes occurred in hWA. In summary, chronic exposure to a β3-AR agonist primes human white adipocytes to respond more potently to adrenergic-mediated lipolysis and enables human brown adipocytes to increase their thermogenic capacity. Disclosure H.J. Lea: None. K.Y. Zhu: None. C. Cero: None. A.M. Cypess: None.