Peptide YY (PYY 3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY 3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY 3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.
A quarter of vagal afferent neurones express the NPY Y2 receptor (Y2R).
Loss of vagal afferent Y2R abrogates the anorectic effects of low dose but not high dose PYY 3-36.
Loss of vagal Y2R accelerates gastric emptying and alters meal patterning, leading to smaller, faster and more frequent meals.
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