Nebivolol induces, via ß3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes.

OBJECTIVES: Most ß-blockers may induce weight gain, dysglycemia, and dyslipidemia. Nebivolol is a third-generation ß1-blocker with vasodilating properties mediated by ß3 adrenergic receptors (ß3AR). We investigated whether nebivolol is able to induce ß3AR-mediated lipolysis, uncoupling protein 1 (UCP1), and size-reduction in human adipocytes. METHODS: Human visceral (n = 28) and subcutaneous adipose tissue (n = 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 ß3AR 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 ß3AR antagonist, suggesting that nebivolol acts through ß3AR in human adipocytes. Interestingly, in human adipocytes, nebivolol activated UCP1, PPARγ coactivator-1α (PGC-1α) and cytochrome c (CYCS) gene expression in a p38 MAPK-dependent manner. Using propranolol (ß1 and ß2 antagonist) together with nebivolol we showed that the induction of these genes was still present suggesting again ß3AR activation. Moreover, nebivolol significantly reduced the diameter of lipid droplets in cultured adipocytes. CONCLUSION: In summary, nebivolol, through ß3AR, 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 ß3 agonist activity and the consequent induction of thermogenic program in human adipocytes.