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Background: Drugs that safely promote weight loss are required to treat the obesity crisis. The gut hormone peptide YY 3-36 (PYY3-36) is secreted post-prandially to suppress appetite via the Y2 receptor (Y2R). However, it is unclear whether PYY3-36 acts directly on the Y2R in the hypothalamic arcuate nucleus (ARC) or the afferent vagus nerve to inhibit food intake. Understanding the pathways by which PYY3-36 mediates its anorectic effects may facilitate the therapeutic targeting of this system. Methods: Y2R knockdown in the ARC (ARC-Y2R-KD) was achieved by stereotactic injection of Cre-expressing adeno-associated virus (AAV-Cre) in Y2R-flox C57Bl/6 mice. Y2R KD in the vagus was achieved by bilateral microinjection of AAV-Cre into the nodose ganglia (NG), where the cell bodies of vagal afferents reside. An alternative germline model of sensory nerve Y2R knockdown was generated using Nav1.8-Cre mice crossed with the Y2R-flox strain (Nav1.8-Y2R-KD). Feeding behaviour over 10 days in metabolic cages and the effects of endogenously released (after oral gavage of a nutrient bolus) or exogenously-administered PYY3-36 were investigated. Results: NG-Y2R-KD animals had 60% reduction in NG Y2R mRNA but remained responsive to cholecystokinin, a positive control of vagal functionality. This is the first example of receptor specific adult vagal deafferentation in mice. The Nav1.8-Y2R-KD model achieved 30% receptor KD. Feeding patterns in the ARC-Y2R-KD and NG-Y2R-KD groups were highly different from their controls, with smaller, faster meals in the KD groups. The anorectic effects (at the next meal) of endogenous PYY3-36 were attenuated in NG-Y2R-KD. Low dose exogenous PYY3-36 at 5 µg/kg significantly reduced 2h post injection food intake (FI) in the control groups (n=8; P=0.045) but this was abrogated in the NG-Y2R-KD group. This pattern was mirrored in the Nav1.8-Y2R-KD model: low dose PYY3-36 significantly reduced FI 1h post-IP compared to vehicle in controls (-0.19±0.05 g; P =0.036; n=8) but not in the Nav1.8-Y2R-KD (-0.004±0.111 g; n=3). Peripherally-administered PYY3-36 at a high dose (30 µg/kg) decreased FI in all groups, including ARC-Y2R-KD. Summary: These results suggest that endogenous PYY3-36 modulates meal patterning. The vagus nerve mediates physiological PYY3-36 signalling but alternative pathways, not exclusively via the ARC, may be more important in mediating its pharmacological effects. This is relevant for the design of more effective weight loss agents.

SAT-607 The Vagus Nerve and the Hypothalamus Mediate Different Aspects of the Anorectic Effects of PYY3-36