Obesity is a key risk factor for atrial fibrillation (AF), yet the molecular mechanisms linking diet-induced obesity to AF remain unclear. Using a “two-hit” mouse model combining chronic high-fat diet and acute sympathetic activation, we investigated how obesity promotes AF. Electrocardiography showed that obesity and sympathetic stimulation synergize during intracardiac tachypacing to induce AF. At the cellular level, atrial myocytes from obese mice exhibited delayed afterdepolarizations following adrenergic stimulation, implicating disrupted Ca 2+ dynamics. Despite unchanged expression of key Ca 2+ -handling proteins, including SERCA and phospholamban (PLN), we observed reduced PLN phosphorylation in obese mice, suggesting decreased SERCA activity, yet atrial myocytes from obese mice showed a change in the Ca 2+ transient decay that is similar to that induced by allosteric SERCA activators. Adrenergic stimulation increased Ca 2+ transient amplitude without altering reuptake kinetics. Transcriptomic analysis revealed upregulation of neuronatin, a protein implicated in obesity and known to stimulate SERCA activity. Our findings suggest that obesity facilitates SERCA activation independently from allosteric PLN regulation, and adrenergic stimulation facilitates AF conversion through arrhythmogenic Ca 2+ -induced Ca 2+ release gain in atrial myocytes. Overall, we provide evidence that obesity prompts PLN-independent SERCA activation, and targeting this molecular mechanism may prove effective for treating obesity-induced AF.
Carlos Cruz Cortes (Sun,) studied this question.