Abstract 1617: Nebivolol Induces Lipolysis and Uncoupling Protein 1 Expression in Ex-vivo Human Visceral Adipocytes

Introduction and Hypothesis. Selective β1 blockers have metabolic side effects such as increasing adiposity, dyslipidemia, and dysglycemia. Nebivolol (a racemic mixture of D- and L-enantiomers) is a β1 blocker with vasodilatatory activity mediated through β3 adrenergic receptors (ADRB3) because of agonist activity of the L-enantiomer. Nebivolol appers to lack the adverse metabolic side effects of other β1 blockers. In this study we examined whether nebivolol was able to induce ADRB3-mediated lipolysis and UCP1 expression, key steps in the use of fatty acids for thermogenesis.

Methods. Human visceral mature adipocytes were isolated from omental adipose tissue obtained during elective abdominal surgery (n=20). Gene expression of ADRB1, ADRB2, ADRB3, and uncoupling protein 1 (UCP1), and adipocyte markers were analysed. ADRB3 were also investigated by western blotting. The effects of isoproterenol, ADRB3 agonists (CL316243, BRL37344), ADBR1 blocker (metoprolol), ADRB3 antagonist (SR59230A), nebivolol (D and L mixture as well as both pure enantiomers) on lipolysis (free glycerol production) and UCP1 expression (evaluated by Real Time PCR-TaqMan assay) were studied in vitro.

Results. Ex-vivo tissue and adipocytes expressed all ADRB receptors, hormone sensitive lipase, and adipocyte markers (adiponectin and leptin). ADRB3 mRNA and protein were expressed in variable amounts. As expected, isoproterenol and ADRB3 agonists induced frank lipolysis whereas non-vasodilating β1 blockers did not. ADBR3 antagonist did not induce lipolysis. Nebivolol induced significant lipolysis (about 2.8-fold, p=0.026) that was mediated by the L-enantiomer (about 50% of the isoproterenol-induced lipolysis at same concentrations). Pre-incubation for 30’ with SR59230A induced a blockade of the lipolytic effects of L-nebivolol and nebivolol. Only nebivolol was able to induce UCP1 gene expression (about 3-fold, P=0.032).

Conclusions. Nebivolol activates ADRB3-mediated lipolysis and induces UCP1 gene expression in human visceral adipocytes, a pathway known to lead to thermogenesis and weight loss. Treatment of obese hypertensive patients with nebivolol reduce blood pressure but also could induce positive metabolic effect acting on visceral adipose tissue.