Objectives: Most β-blockers may induce weight gain, dysglycemia, and dyslipidemia. Nebivolol is a third-generation β1-blocker with vasodilating properties mediated by β3 adrenergic receptors (β3AR). We investigated whether nebivolol is able to induce β3AR-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 β3AR 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 β3AR antagonist, suggesting that nebivolol acts through β3AR 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 (β1 and β2 antagonist) together with nebivolol we showed that the induction of these genes was still present suggesting again β3AR activation. Moreover, nebivolol significantly reduced the diameter of lipid droplets in cultured adipocytes.
Conclusion: In summary, nebivolol, through β3AR, 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 β3 agonist activity and the consequent induction of thermogenic program in human adipocytes.
aInternal Medicine and Geriatrics, Department of Clinical and Molecular Sciences, Ospedale ‘U. Sestilli’, Italian National Research Center on Aging IRCCS-INRCA and University ‘Politecnica delle Marche’ Ancona
bDepartment of Surgery, University Hospital of Ancona
cDepartment of Urology, University Hospital of Ancona, Ancona, Italy
Correspondence to Professor Riccardo Sarzani, MD, Ph.D, Internal Medicine and Geriatrics, Department of Clinical and Molecular Sciences, University ‘Politecnica delle Marche’, Via Tronto 10/A, Ancona 60126, Italy. Tel: +39 071 5964595; fax: +39 071 889232; e-mail: firstname.lastname@example.org
Abbreviations: β3AR, β3 adrenergic receptor; CYCS, cytochrome c; PGC-1α, PPARγ coactivator-1α; SVF, stromal vascular fraction; UCP1, uncoupling protein 1
Received 18 April, 2013
Revised 2 August, 2013
Accepted 12 September, 2013
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