High fat diet decreases glucose‐dependent modulation of 5‐HT responses in gastrointestinal vagal afferent neurons

Abstract

5‐hydroxytryptamine (5‐HT) release from intestinal enteroendocrine cells activates gastrointestinal (GI) vagal afferent neurons inducing a vagally‐mediated gastric relaxation and satiation. Since glucose modulates the response of GI vagal afferent neurons to 5‐HT, we hypothesized that exposure to a high fat diet (HFD) may affect these actions of glucose.Rats were fed control or HFD (18% or 60% kcal from fat, respectively) from 4 weeks of age for 8 weeks. Electrophysiological recordings were made from acutely dissociated GI vagal afferent neurons and immunocytochemical studies assessed the neuronal distribution of 5‐HT3 receptors.5‐HT induced an inward current which was sensitive to glucose in the majority (12/13) of control GI vagal afferent neurons. The proportion of 5‐HT‐sensitive GI vagal afferent neurons was unaffected by HFD (5/6 & 5/6 neurons after 1 & 8 weeks respectively, P>;0.05 vs control). HFD attenuated glucose modulation of the 5‐HT response; after 1 week, glucose modulated the 5‐HT response in only 1/5 HFD neurons (151, 183 and 354pA in response to 2.5, 5, and 10mM glucose) while after 8 weeks, 0/5 HFD neurons were affected by glucose. Furthermore, after HFD glucose was unable to alter the proportion of membrane‐associated 5‐HT3 receptors (28±0.8% at 2.5mM to 29±0.7% at 20mM glucose) in contrast to previous control studies (24±1.8% at 2.5mM to 37±2.6% at 20mM glucose).These data suggest that, while exposure to HFD does not affect the responsiveness of GI vagal afferent neurons to 5‐HT, it diminishes the ability of glucose to regulate 5‐HT responses. This suggests that glucose‐dependent vagal afferent signaling is compromised by relatively short periods of exposure to HFD well in advance of the development of obesity.Supported by NIH DK078364