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We examined the hypothesis that leptin signaling contributes to the atrial fibrosis and atrial fibrillation (AF) evoked by angiotensin II (AngII).Eight-week-old male CL57/B6 (CNT) and leptin-deficient ob/ob mice (Ob) were subcutaneously infused with AngII (2.0 mg/kg per day). Two weeks later, transesophageal burst pacing and an electrophysiological study using isolated perfused hearts were performed. Left-atrial tissues were collected to determine interstitial fibrosis by Masson trichrome staining, and the expressions of mRNAs related to inflammatory profibrotic signals were assessed. Left-atrial fibroblasts were isolated from adult Sprague-Dawley and Zucker rats. The effects of leptin (100 ng/mL) or AngII (100 nmol/L) treatment were evaluated. In CNT-AngII mice, leptin expression in the left atrium was upregulated (P<0.01). Transesophageal burst pacing induced atrial fibrillation in 88% (7/8) of CNT-AngII mice, but not in Ob-AngII mice (0/8; P<0.01). In isolated perfused hearts, atrial fibrillation was induced only in CNT-AngII mice (4/6; 67%). Interatrial conduction time was prolonged in CNT-AngII mice (P<0.01), but not in Ob-AngII mice. The upregulation of collagen 1, collagen 3, transforming growth factor-β1, α-smooth muscle actin, MCP-1, F4/80, and RANTES mRNA, which was seen in CNT-AngII mice, was attenuated in Ob-AngII mice. In cultured Sprague-Dawley rat atrial fibroblasts, AngII treatment increased leptin expression (P<0.01). Addition of leptin increased transforming growth factor-β1, α-smooth muscle actin, MCP-1, and RANTES expressions in Sprague-Dawley rat atrial fibroblasts, but not in Zucker rat atrial fibroblasts.Our results demonstrate for the first time that leptin signaling is essential for the development of atrial fibrosis and atrial fibrillation evoked by AngII.