Liraglutide Ameliorates Atrial Fibrillation in Association with Enhanced Adiponectin Signaling in Epicardial Adipose...

Atrial fibrillation (AF) is associated with obesity and epicardial adipose tissue (EAT) dysfunction. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide, exert cardiovascular benefits, the underlying mechanisms, particularly those related to EAT and adipokine signaling remain unclear.

AF rat model was established using acetylcholine-CaCl₂ infusion. Model rats were treated with liraglutide or saline, and cardiac functions were assessed using electrocardiography (ECG) and echocardiography. Myocardial and EAT morphology was examined histologically. The levels of adiponectin (ADPN), inflammatory factors, and lipids were measured using enzyme-linked immunosorbent assay, and the protein levels of ADPN and its receptor were evaluated through western blotting. In vitro, 3T3-L1 adipocytes were treated with TNF-α to simulate a model of dysregulated lipid metabolism and inflammation. Subsequently, HL-1 cells were treated with the conditioned medium from 3T3-L1 cells. The interaction between adipocytes and cardiomyocytes was evaluated by assessing HL-1 cell proliferation, apoptosis, and levels of ADPN and inflammatory factors.

Liraglutide significantly reduced the duration of AF, improved cardiac function (decreased E/E', increased ejection fraction and LAACF), ameliorated myocardial fibrosis, and restored EAT morphology. Mechanistically, liraglutide specifically enhanced ADPN secretion and upregulated AdipoR1 expression in EAT, reduced interleukin (IL)-6 and IL-1β levels, and decreased free fatty acid (FFA) and triglyceride content. Notably, using an ADPN-neutralizing antibody in vitro, we demonstrated that ADPN mediates the protective effects of liraglutide on cardiomyocytes, suggesting the role of EAT-derived ADPN signaling.

Liraglutide alleviates AF by increasing ADPN secretion and AdipoR1 expression in the EAT, improving local lipid metabolism, and attenuating inflammation. These findings establish a correlational association between liraglutide treatment, favorable modulation of the EAT phenotype, and AF amelioration, and propose a testable hypothesis that adiponectin signaling is involved in liraglutide-mediated cardioprotection.