RF36 | PSUN79 Prolonged Stimulation of β-Adrenergic Receptors in Human Brown and White Adipocytes Increases and then Decreases Metabolic Activity

Abstract

Background Obesity results from excess adipose triglyceride storage and leads to multiple life-threatening complications that may be amenable to novel pharmacological therapies. Both human white and brown adipocytes express β1-, β2-, and β3-adrenergic receptors (β-AR's), and stimulation of each activates converging signaling pathways that regulate essential metabolic and cellular functions. Clinical data indicate that acute and chronic stimulation of the β3-AR with the selective agonist mirabegron increases lipolysis and thermogenesis, thereby making β3-AR activation a promising target to improve obesity-related metabolic disease. Purpose In this study, we evaluated in vitro the short-term and prolonged activation of β3-ARs via mirabegron and compared the effects to the activation of β1- and β2-AR. Methods Functional cellular assays such as lipolysis and cellular respiration, were measured in immortalized human white (hWA) and brown (hBA) adipocytes derived from the superficial and deep neck depots, respectively. Cells were treated for 6 h (short-term) and 24 h (prolonged) with mirabegron (β3-AR agonist), dobutamine (β1-AR agonist), terbutaline (β2-AR agonist) and isoproterenol (non-selective β-AR agonist). One-way ANOVA was used for statistical analysis. Findings In hWA, only short-term activation of the β2-AR induced lipolysis (1.8-fold increase, P=0.0002), while in hBA, both the β2-AR (1.5-fold increase, P=0.04) and β3-AR (1.6 fold increase, P=0.002) increased lipolysis with 6h treatment, as compared to the vehicle. By 24h, lipolysis was blunted in both cell types, likely due to agonist-induced desensitization and downregulation. Distinct from the lipolytic effects ofβ-AR activation, the basal oxygen consumption rate (OCR) was not significantly different among hBA and hWA treated acutely and chronically with each of the three selective β-ARs and positive control isoproterenol. However, in hBA only, prolonged activation of all three β-AR's lowered maximal mitochondrial respiration (isoproterenol: 25% decrease, P=0.0004; dobutamine: 25% decrease, P=0.0003; terbutaline: 26% decrease, P=0.0004; mirabegron: 38% decrease, P<0.0001, respectively). No significant changes in OCR parameters were detected in hWA. Conclusion In hBA, acute stimulation of either the β2-AR or β3-AR induces lipolysis. Prolonged exposure to β-agonists comparably lowers maximal cellular respiration, suggesting that all β-AR's are subject to agonist-induced desensitization. Moreover, continuous activation of lipolysis may deplete the intracellular fatty acid pool necessary for mitochondrial oxidative respiration. These responses will need to be addressed before novel adrenergic activators can be utilized to reduce triglyceride stores and treat obesity-related metabolic disease. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:00 p.m. - 1:05 p.m.