Effect of high-fat diet on mechanosensitive transient receptor potential channel activation in vagal afferent neurons

Mechanical stimulation of the gastrointestinal tract is an important stimulus of satiety and can be transduced by transient receptor potential (TRP) channels. Several studies have revealed attenuated vagally-mediated satiety responses including mechanosensitivity in diet-induced obesity; however, ion channels underlying this hyposensitivity have not been fully understood. This study aimed to examine the effect of chronic high-fat diet on activation of selected mechanosensitive TRP channels in vagal afferents. C57/BL6 mice were fed on either a high-fat or low-fat diet for 6-8 weeks. An increase in the intracellular calcium to hypotonic solution and activators of TRPV1, TRPV4, and TRPA1 was measured in nodose neurons using Ca2+-imaging techniques. Jejunal afferent nerve firing induced by mechanical stimulation and TRP channel agonists was measured using in vitro extracellular multiunit afferent recording. In high-fat diet-fed mice, we observed reduced calcium influx and jejunal afferent response induced by mechanical stimuli and agonists of TRPV4 and TRPA1, but not TRPV1. Our data show diet-induced obesity disrupts the activation of TRPV4 and TRPA1, at both the cellular level and the level of nerve terminals in the small intestine, which may partly explain reduced mechanosensitivity of vagal afferents and may contribute to decreased gut-brain satiety signaling in obesity.