Introduction: The gut hormone peptide YY 3-36 (PYY3-36) is secreted postprandially from intestinal L-cells to signal satiety. Peripheral administration of PYY3-36 suppresses food intake in rodents and humans. PYY3-36-based drugs are therefore promising anti-obesity treatments. It has been proposed that circulating PYY3-36 supresses appetite via the Y2 receptor (Y2R) in the hypothalamic arcuate nucleus (ARC). The vagus nerve, the major link between the gut and the brain, also expresses Y2R but its role in PYY3-36 signalling is poorly understood. We hypothesised that PYY3-36 physiologically reduces food intake by activating vagal afferent signalling and does not activate central appetite/nausea-altering pathways to have an effect.
Methods: We generated an afferent vagus nerve-specific Y2R knockdown (KD) mouse model. Adult Y2RloxP/loxP mice were bilaterally injected in the nodose ganglion (NG) of the vagus nerve with an adenoassociated virus (AAV) encoding the Cre recombinase (AAV-Cre). To study the central Y2R, adult Y2RloxP/loxP mice were bilaterally injected with AAV-Cre in the ARC. Heterozygous littermates injected with a GFP-expressing AAV were used as controls.
Results and Conclusions: Quantification of Y2R mRNA in NG, which contains only the cell bodies of vagal afferents, demonstrated >70% KD of Y2R in AAV-Cre-injected Y2RloxP/loxP mice (NG-Y2R-KD) compared with controls. This is, to our knowledge, the first example of selective Y2R vagal deafferentation. Intraperitoneal injection of PYY3-36 at low dose decreased food intake in control groups, but this effect was abrogated in NG-Y2R-KD. PYY3-36 administration at a high dose resulted in appetite suppression in all experimental groups, including ARC-Y2R-KD. High resolution food intake analysis revealed a significant difference in meal patterning rather than total food intake in the NG-Y2R-KD group. These results suggest that the afferent vagus nerve contributes to mediating the physiological effects of PYY3-36 but that alternative signalling pathways might be more important in mediating its pharmacological effects.