Cholecystokinin (CCK) is a peptide released from the duodenum in response to luminal amino acids and fatty acids which can cause a reduction in food intake, an effect lost after a vagotomy1. Satiety signals, mediated by vagal afferents, can be initiated from the stomach as well as the small intestine. Previously, CCK octapeptide (CCK-8) has been shown to potentiate gastric vagal afferent (GVA) mechanosensitivity2. In diet-induced obesity (DIO) exogenous CCK-8 has a reduced ability to reduce food intake3. We aimed to determine whether CCK-8 loses its ability to modulate GVAs in DIO and if so whether this is reversible on return to a normal diet.Female C57BL/6 mice (8 weeks old) were fed a standard (SLD; 12%, 23%, 65% energy from fat, protein, carbohydrate, N=8) or high fat diet (DIO; 60%, 20%, 20% energy from fat, protein, carbohydrate, N=8) for 24 weeks. A third group were fed a high fat diet for 12 weeks and then returned to SLD for a further 12 weeks (RFD, N=8). Single fibre recordings of GVA mechanoreceptors4 were made before and after exposure to CCK-8 (10-1000pM).The effect of CCK-8 on vagal afferents from all groups of mice is summarised in table 1. In SLD mice, CCK-8 (10-1000pM) potentiated tension (N=4) and mucosal receptor (N=6) responses to stretch (0.5-5g; p<0.05, two-way ANOVA, CCK-8 effect) and mucosal stroking with calibrated von Frey hairs (10-1000mg; p<0.01, two-way ANOVA, CCK-8 effect) respectively. In DIO mice, CCK-8 had no effect on either tension (N=6) or mucosal (N=4) receptor responses to mechanical stimulation (p>0.05, two-way ANOVA, CCK-8 effect). In RFD mice CCK-8 was still unable to potentiate tension receptor mechanosensitivity (N=4, p>0.05, two-way ANOVA, CCK-8 effect), but regained the ability to potentiate mucosal receptor mechanosensitivity (N=3) to the same extent as seen in the SLD mice.In conclusion, the effect of CCK-8 on GVA tension and mucosal receptors is lost in DIO and can only be partially recovered by returning to a SLD, indicating the presence of different mechanisms controlling the GVA modulatory action of CCK-8. Therefore, disruption of the effect of CCK on gastric vagal afferent satiety signals may partially account for the reduced ability of CCK to reduce food intake in DIO. In addition, failure to return to normal upon return to a SLD may explain the difficulty experienced in weight loss management.