Nebivolol induces, via β3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes.

Objectives: Most b-blockers may induce weight gain, dysglycemia, and dyslipidemia. Nebivolol is a third- generation b1-blocker with vasodilating properties mediated by b3 adrenergic receptors (b3AR). We investigated whether nebivolol is able to induce b3AR- mediated lipolysis, uncoupling protein 1 (UCP1), and size- reduction in human adipocytes. Methods: Human visceral (n ¼ 28) and subcutaneous adipose tissue (n ¼ 26) samples were used to obtain differentiated subcutaneous and visceral preadipocytes. Adipocytes were used to verify the effects of nebivolol onlipolysis, uncoupling protein 1 (UCP1) and other genes of the thermogenic program. Results: Lipolysis was induced by isoproterenol and specific b3AR agonist, as expected,and also by nebivolol at 100 nmol/l and by its L-enantiomer at 10 nmol/l (P < 0.01). Nebivolol-mediated lipolysis was blocked by SR59230A, a specific b3AR antagonist, suggesting that nebivolol acts through b3AR in human adipocytes. Interestingly, in human adipocytes, nebivolol activated UCP1, PPARg coactivator-1a (PGC-1a) and cytochrome c (CYCS) gene expression in a p38 MAPK–dependent manner. Using propranolol (b1 and b2 antagonist) together with nebivolol we showed that the induction of these genes was still present suggesting again b3AR activation. Moreover, nebivolol significantly reduced the diameter of lipid droplets in cultured adipocytes. Conclusion: In summary, nebivolol, through b3AR, is able to induce lipolysis and promote thermogenic and mitochondrial genes. The induction of lipolysis and the thermogenic program could explain the reduction of lipid droplets size. In conclusion, the lower dysmetabolic effects of nebivolol in humans may depend on its b3 agonist activity and the consequent induction of thermogenic program in human adipocytes.