Apelin Contributes to Chronic High‐Fat Diet Induced Vagal Dysfunction in Rats

Abstract

Gastric accommodation response (GAR) is the change in the size of the gastric compartment in response to the ingested meal which is known to be mediated both by enteric and autonomic nervous system that substantially involves the vago‐vagal reflexive neurocircuitry. In addition to induce obesity, exposure to prolonged high‐fat diet (HFD) has been demonstrated to impair meal‐induced satiety signals in rodents. Apelin and APJ receptor exhibit a widespread distribution within central nervous system (CNS) including the autonomic centers regulating gastrointestinal (GI) functions. Besides CNS, apelin is expressed in adipose tissue, moreover, serum apelin levels were found significantly higher in obese humans. Administration of novel neuropeptide apelin has been shown to abolish autonomic and sensory vagal functions through APJ receptor in rats, however, the relevant mechanism remains unknown. This study was designed to investigate the role of central apelin in vagal dysfunction induced by HFD. Fourweek old male Sprague‐Dawley rats were fed with HFD or control diet (60% and 13.5% energy by fat, respectively) for 12 weeks. The experiments were performed in fasted rats placed on stereotaxic frame under urethane anesthesia. Vagal trigon in the caudal part of the medulla was exposed by removing the atlanto‐occipital musculature and membranes. To evaluate GAR, intragastric pressure was gradually increased through a balloon catheter inserted in fundus which was inflated with 6 ml of prewarmed saline at a rate of 1 ml min−1. The pressure‐induced changes in gastric tone were monitored through a pair of strain gage transducers serosally implanted in corpus and fundus. Simultaneously, electrocardiography was recorded to assess sympatho‐vagal balance through heart rate variability (HRV). Low frequency (LF; 0.05–0.75 Hz) and high frequency (HF; 0.75–2.5 Hz) oscillatory components were quantified to monitor vagal outflow and sympatho‐vagal balance. After basal measurements, APJ receptor antagonist F13A (10 nmol/2μL) applied onto the surface of fourth ventricle following a recovery period for 60 min, the measurements then were repeated on the same animal. Compared with the rats consumed control diet, 12 weeks feeding of HFD significantly increased body weight and visceral adiposity, while remarkably blunting the intragastric pressure‐induced GAR both in fundus and corpus (p<0.05) (n=4). In control rats, increased intragastric pressure caused a significant reduction in vagal signaling (HF); whereas, sympatho‐vagal balance (LF:HF) was increased (p<0.05) (n=4). In contrast, these autonomic responses were substantially attenuated in HFD rats (p<0.05) (n=4). The HFD‐induced changes in GAR and HRV significantly attenuated by preadministration of F13A. The present data suggest that central endogenous apelin may play a role HDF‐induced vagal dysfunction. In conclusion, the apelinergic system, particularly in vagal neurocircuitry appears to be a potential pharmacological target for GI disorders related to obesity and autonomic dysfunction.Support or Funding InformationThe Scientific and Technological Research Council of Turkey (TUBITAK; Research Program 1001, 217S644)