Epicardial adipose tissue Glucagon-like peptide-1 receptor upregulation in human atrial fibrillation might be functionally offset by accompanying Phosphodiesterase-4 upregulation

Background Glucagon-like peptide (GLP)-1 receptor (GLP-1R) agonists exert multiple beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction, including possible protection against arrhythmogenesis and atrial fibrillation (AFib). GLP-1R is a G protein-coupled receptor (GPCR) that activates adenylyl cyclase (AC) to stimulate cyclic adenosine monophosphate (cAMP) synthesis. cAMP exerts various actions via Protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac)1/2 (1). At the same time, cAMP actions in cells are terminated by the phosphodiesterase (PDE) family of enzymes, with PDE4 being upregulated in several inflammatory states (1). Adiponectin (ADPN) and osteopontin (OPN) are two important adipokines secreted by the adipocytes of epicardial adipose tissue (EAT), which also express GLP-1R, to suppress or enhance inflammation, respectively (2). OPN has been directly linked to human AFib pathogenesis via macrophage M1 activation and promotion of atrial fibrosis (3). Study objective: Herein, we investigated a) EAT GLP-1R and PDE4 levels in EAT biopsies of AFib vs. non-AFib patients undergoing cardiac surgery, and b) the signaling mechanisms of GLP-1R-dependent regulation of ADPN and OPN secretion from human visceral white adipose tissue (VWAT) cells (as a cell model proxy to EAT adipocytes) in culture. Methods & Results Using levels in subcutaneous adipose tissue (SAT) as control for the comparisons, GLP-1R protein levels were found significantly elevated in peri-coronary artery EAT of AFib patients compared to non-AFib patients. In contrast, PDE4 protein levels were markedly elevated in EAT vs. SAT in both groups, i.e., irrespective of AFib presence. In human VWAT cells cultured in vitro, GLP-1R activation with liraglutide (or semaglutide) stimulated ADPN secretion via cAMP elevation and subsequent Epac1/2 activation, since Epac inhibition with ESI-09 abolished GLP-1R-induced ADPN secretion. In contrast, OPN synthesis and secretion induced by pretreatment with the pro-inflammatory adipokine interleukin (IL)-1beta was suppressed by liraglutide-activated GLP-1R. Finally, treatment of human VWAT adipocytes with IL-1beta upregulated PDE4 and inhibited GLP-1R-dependent ADPN secretion. Pretreatment with the PDE4-selective inhibitor nerandomilast rescued the suppressed GLP-1R-induced ADPN secretion by IL-1beta. Conclusions GLP-1R is upregulated in human EAT during AFib to possibly help protect the cardiomyocytes, which EAT is in physical contact with, against EAT-secreted adipokine triggers of arrhythmogenesis/AFib. However, inflammation also upregulates PDE4 in human EAT, an enzyme that opposes GLP-1R signaling via cAMP, thereby potentially compromising this cardioprotective capability of GLP-1R in terms of adipokine regulation. Combining a GLP-1R agonist with a PDE4 inhibitor might overcome this obstacle and enhance efficacy of GLP-1R agonist drugs for AFib treatment.