Obesity including metabolic syndrome is an independent risk factor of atrial fibrillation (AF). Although hyperleptinemia is usually a characteristic of obese subjects, the relationship with atrial fibrosis and AF is unknown. We tested the hypothesis that high‐fat diet (HFD)‐induced hyperleptinemia exacerbates atrial fibrosis and AF.

Eight‐week‐old male C57BL/6 (WT) and leptin‐deficient ob/ob (Ob) mice were treated with a normal‐fat diet (NFD) or 60% HFD. After 8 weeks, transesophageal burst pacing and electrophysiological study using isolated perfused hearts were performed and left atrial (LA) tissues were collected for histological analysis, hydroxyproline assay, and reverse transcription‐polymerase chain reaction. HFD treatment increased body weight in both WT and Ob mice compared with NFD (both P < 0.01). In WT‐HFD mice, hyperleptinemia was observed as expected. While transesophageal burst pacing invariably induced AF (8/8, 100%) in WT‐HFD mice, AF was induced less frequently (1/8, 12.5%) in Ob‐HFD mice (P < 0.01). In isolated perfused hearts, the interatrial conduction time was prolonged in WT‐HFD mice, but not in Ob‐HFD mice (P < 0.05). Masson's trichrome staining and the hydroxyproline assay revealed interstitial LA fibrosis in WT‐HFD mice, which was not observed in Ob‐HFD mice (P < 0.05). Upregulation of collagen1, collagen3, α‐smooth muscle actin, tumor necrosis factor‐α, and monocyte chemoattractant protein‐1 mRNA levels was noted in WT‐HFD mice LA, but attenuated in Ob‐HFD mice LA.

Our findings suggest that hyperleptinemia exacerbates HFD‐mediated atrial fibrosis and AF. Inhibition of leptin signaling may become a novel therapeutic target to prevent obesity‐related AF.