Nebivolol induces, via beta 3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes

作者：Bordicchia Marica; Pocognoli Antonella; D'Anzeo Marco; Siquini Walter; Minardi Daniele; Muzzonigro Giovanni; Dessi Fulgheri Paolo; Sarzani Riccardo^*

来源：Journal of Hypertension, 2014, 32(2): 389-396.

DOI：10.1097/HJH.0000000000000024

• 3 adrenergic receptor
• human adipocytes
• nebivolol
• uncoupling protein

Objectives:Most -blockers may induce weight gain, dysglycemia, and dyslipidemia. Nebivolol is a third-generation 1-blocker with vasodilating properties mediated by 3 adrenergic receptors (3AR). We investigated whether nebivolol is able to induce 3AR-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 3AR agonist, as expected,and also by nebivolol at 100nmol/l and by its L-enantiomer at 10nmol/l (P<0.01). Nebivolol-mediated lipolysis was blocked by SR59230A, a specific 3AR antagonist, suggesting that nebivolol acts through 3AR in human adipocytes. Interestingly, in human adipocytes, nebivolol activated UCP1, PPAR coactivator-1 (PGC-1) and cytochrome c (CYCS) gene expression in a p38 MAPK-dependent manner. Using propranolol (1 and 2 antagonist) together with nebivolol we showed that the induction of these genes was still present suggesting again 3AR activation. Moreover, nebivolol significantly reduced the diameter of lipid droplets in cultured adipocytes.Conclusion:In summary, nebivolol, through 3AR, 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 3 agonist activity and the consequent induction of thermogenic program in human adipocytes.

• 出版日期2014-2