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Melatonin has been proven to have antiarrhythmic potential; however, several studies have recently challenged this view. Herein, using a mouse model of obesity‐induced atrial fibrillation (AF), we tentatively explored whether exogenous melatonin supplementation could increase AF susceptibility in the context of obesity. We observed that an 8‐week drinking administration of melatonin (60 µg/ml in water) induced a greater susceptibility to AF in obese mice, although obesity‐induced structural remodeling was alleviated. An investigation of systemic insulin sensitivity showed that melatonin treatment improved insulin sensitivity in obese mice, whereas it inhibited glucose‐stimulated insulin secretion. Notably, melatonin treatment inhibited protein kinase B (Akt) signaling in the atria of obese mice and palmitate‐treated neonatal rat cardiomyocytes, thereby providing an AF substrate. Melatonin increased lipid stress in obesity, as evidenced by elevated lipid accumulation and lipolysis‐related gene expression, thus contributing to the impairment in atrial Akt signaling. Taken together, our results demonstrated that melatonin could increase AF susceptibility in obesity, probably due to increased lipid stress and resultant impairment of atrial Akt signaling. Our findings suggest that special precautions should be taken when administering melatonin to obese subjects. [ABSTRACT FROM AUTHOR]

Necroptosis, a novel programmed cell death, plays a critical role in the development of fibrosis, yet its role in atrial fibrillation (AF) remains elusive. Mounting evidence demonstrates that aerobic exercise improves AF‐related symptoms and quality of life. Therefore, we explored the role of necroptosis in AF pathogenesis and exercise‐conferred cardioprotection. A mouse AF model was established either by calcium chloride and acetylcholine (CaCl2‐Ach) administration for 3 weeks or high‐fat diet (HFD) feeding for 12 weeks, whereas swim training was conducted 60 min/day, for 3‐week duration. AF susceptibility, heart morphology and function and atrial fibrosis were assessed by electrophysiological examinations, echocardiography and Masson's trichrome staining, respectively. Both CaCl2‐Ach administration and HFD feeding significantly enhanced AF susceptibility (including frequency and duration of episodes), left atrial enlargement and fibrosis. Moreover, protein levels of necroptotic signaling (receptor‐interacting protein kinase 1, receptor‐interacting protein kinase 3, mixed lineage kinase domain‐like protein and calcium/calmodulin‐dependent protein kinase II or their phosphorylated forms) were markedly elevated in the atria of AF mice. However, inhibiting necroptosis with necrostatin‐1 partly attenuated CaCl2‐Ach (or HFD)‐induced fibrosis and AF susceptibility, implicating necroptosis as contributing to AF pathogenesis. Finally, we found 3‐week swim training inhibited necroptotic signaling, consequently decreasing CaCl2‐Ach‐induced AF susceptibility and atrial structural remodeling. Our findings identify necroptosis as a novel mechanism in AF pathogenesis and highlight that aerobic exercise may confer benefits on AF via inhibiting cardiac necroptosis. [ABSTRACT FROM AUTHOR]