Paradoxical SERCA dysregulation contributes to atrial fibrillation in a model of diet-induced obesity

Obesity is a major risk factor for atrial fibrillation (AF) the most common serious cardiac arrhythmia, but the molecular mechanisms underlying diet-induced AF remain unclear. In this study, we subjected mice to a chronic high-fat diet and acute sympathetic activation ('two-hit' model) to study the mechanisms by which diet-induced obesity promotes AF. Surface electrocardiography revealed that diet-induced obesity and sympathetic activation synergize during intracardiac tachypacing to induce AF. At the cellular level, diet-induced obesity and acute adrenergic stimulation facilitate the formation of delayed afterdepolarizations in atrial myocytes, implicating altered Ca²⁺ dynamics as the underlying cause of AF. We found that diet-induced obesity does not alter the expression of major Ca²⁺-handling proteins in atria, including the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), a major component of beat-to-beat Ca²⁺ cycling in the heart. Paradoxically, obesity reduces phospholamban phosphorylation, suggesting decreased SERCA activity, yet atrial myocytes from obese mice showed a significantly increased Ca²⁺ transient amplitude and SERCA-mediated Ca²⁺ uptake. Adrenergic stimulation further increases the Ca²⁺ transient amplitude but does not affect Ca²⁺ reuptake in atrial myocytes from obese mice. Transcriptomics analysis showed that a high-fat diet prompts upregulation of neuronatin, a protein that has been implicated in obesity and is known to stimulate SERCA activity. We propose a mechanism in which obesity primes SERCA for paradoxical activation, and adrenergic stimulation facilitates AF conversion through a Ca²⁺-induced Ca²⁺ release gain in atrial myocytes. Overall, this study links obesity, altered Ca²⁺ signaling, and AF, and targeting this mechanism may prove effective for treating obesity-induced AF.