Association of the chemerin-CMKLR1 with atrial potassium current dysregulation and atrial fibrillation in obese mice

Obesity is an established risk factor for atrial fibrillation (AF) and is associated with hypersecretion of the adipokine chemerin. Chemerin has been linked to the AF initiation and progression predominantly through Chemokine-like receptor 1(CMKLR1)-mediated signaling. This study aimed to elucidate how activation of the chemerin-CMKLR1 contributes to atrial potassium current dysregulation in obesity-related AF. Male C57BL/6J mice were divided into high-fat diet (HFD) and low-fat diet (LFD) group. Action potentials and potassium currents were recorded by whole-cell patch-clamp electrophysiology. HFD mice exhibited significantly increased susceptibility to AF. Atrial myocytes from HFD mice showed marked shortening of action potential duration, primarily due to an increase in peak repolarizing potassium current (Ik,peak). The rise in IK,peak density was attributed to concurrent remodeling of its components, the transient outward potassium current (Ito) and the ultrarapid delayed rectifier potassium current (IKUr). Ito density increased from 30.13 ± 0.76 pA/pF to 35.42 ± 0.70 pA/pF at +70 mV, accompanied by a leftward shift of steady-state activation, a rightward shift of steady-state inactivation, faster recovery from inactivation, and upregulated Kv4.3 and KChIP2 expression. IKUr density increased from 23.95 ± 1.95 pA/pF to 30.24 ± 0.97 pA/pF at +70 mV, consistent with elevated Kv1.5 expression. These electrophysiological changes were paralleled by upregulated protein abundance of chemerin and its receptor CMKLR1 in atrial myocytes, suggesting activation of the chemerin-CMKLR1 in obese mice. Obesity-associated activation of the chemerin-CMKLR1 promotes pathological potassium current remodeling, shortens atrial APD, and contributes to obesity-related AF.