Modulatory effect of methanandamide on gastric vagal afferent satiety signals depends on nutritional status

Abstract

Significance Statement: Gastric vagal afferent responses to tension are dampened in high fat diet-induced obesity. Endocannabinoids are known to dose-dependently inhibit and excite gastric vagal afferents but their effect on gastric vagal afferents in diet-induced obesity are unknown. In individual gastric vagal afferent neurons of diet-induced obese mice the co-expression of components of the endocannabinoid system, including CB1, GHSR, TRPV1, and FAAH, was increased compared to lean mice. In high fat diet-induced obese mice methanandamide only inhibited gastric vagal afferent responses to tension, possibly due to the observed change in balance of receptors, hormones, and breakdown enzymes in this system. Collectively, these data suggest endocannabinoid signalling, by gastric vagal afferents, is altered in diet-induced obesity which may impact satiety and gastrointestinal function. Abstract: Gastric vagal afferents (GVAs) play a role in appetite regulation. The endocannabinoid anandamide (AEA) dose dependently inhibits and excites tension sensitive GVAs. However, it is also known that high fat diet (HFD) feeding alters GVA responses to stretch. The aim of this study was to determine the role of AEA in GVA signalling in lean and HFD-induced obese mice. Male C57BL/6 mice were fed (12wks) a standard laboratory diet (SLD) or HFD. Protein and mRNA expression of components of the cannabinoid system was determined in individual GVA cell bodies and the gastric mucosa. An in vitro GVA preparation was used to assess the effect of methanandamide (mAEA) on tension sensitive GVAs and the second messenger pathways involved. In individual GVA cell bodies, cannabinoid 1 (CB1) and ghrelin (GHSR) receptor mRNA was higher in HFD- compared to SLD-mice. Conversely, gastric mucosal AEA and ghrelin protein levels were lower in HFD- compared to SLD-mice. In SLD-mice, mAEA exerted dose-dependent inhibitory and excitatory effects on tension sensitive GVAs. Only an inhibitory effect of mAEA was observed in HFD-mice. The excitatory effect of mAEA was dependent on CB1, transient receptor potential vanilloid 1 (TRPV1) and protein kinase C. Conversely, the inhibitory effect was dependent on CB1, GHSR, TRPV1, and protein kinase A. Endocannabinoids, acting through CB1 and TRPV1, have a pivotal role in modulating GVA satiety signals depending on the second messenger pathway utilised. In HFD-mice only an inhibitory effect was observed. These changes may contribute to the development and/or maintenance of obesity.