Olodaterol promotes thermogenesis in brown adipocytes via regulation of the 2-AR/cAMP/PKA signaling pathway

The escalating incidence of metabolic pathologies such as obesity and diabetes mellitus underscores the imperative for innovative therapeutics targeting lipid metabolism modulation. Within this context, augmenting thermogenic processes in adipose cells emerges as a viable therapeutic approach. Given the limitations of previous 83-adrenergic receptor (83 -AR) agonist treatments in human diseases, there is an increasing focus on therapies targeting the 82-adrenergic receptor (82 -AR). Olodaterol (OLO) is a potent 82 -AR agonist that is a potential novel pharmacological candidate in this area. Our study explores the role and underlying mechanisms of OLO in enhancing brown adipose thermogenesis, providing robust evidence from in vitro and in vivo studies. OLO demonstrated a dose -dependent enhancement of lipolysis, notably increasing the expression of Uncoupling Protein 1 (UCP1) and raising the rate of oxygen consumption in primary brown adipocytes. This suggests a significant increase in thermogenic potential and energy expenditure. The administration of OLO to murine models noticeably enhanced cold -induced nonshivering thermogenesis. OLO elevated UCP1 expression in the brown adipose tissue of mice. Furthermore, it promoted brown adipocyte thermogenesis by activating the 82AR/cAMP/PKA signaling cascades according to RNA sequencing, western blotting, and molecular docking analysis. This investigation underscores the therapeutic potential of OLO for metabolic ailments and sheds light on the intricate molecular dynamics of adipocyte thermogenesis, laying the groundwork for future targeted therapeutic interventions in human metabolic disorders.