title: Nebivolol induces, via β3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Marica
authors.initials: M
authors.lastname: Bordicchia
authors.forename: Antonella
authors.initials: A
authors.lastname: Pocognoli
authors.forename: Marco
authors.initials: M
authors.lastname: D'Anzeo
authors.forename: Walter
authors.initials: W
authors.lastname: Siquini
authors.forename: Daniele
authors.initials: D
authors.lastname: Minardi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muzzonigro
authors.forename: Paolo
authors.initials: P
authors.lastname: Dessì-Fulgheri
authors.forename: Riccardo
authors.initials: R
authors.lastname: Sarzani
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D001578:Benzopyrans / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism*; D000068577:Nebivolol; D011412:Propanolamines / Q000494:pharmacology; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects* / Q000378:metabolism*; D000071256:Uncoupling Protein 1
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058671:Adrenergic beta-1 Receptor Antagonists; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; D000068577:Nebivolol