The obesity epidemic is a critical and global public health burden. Drugs that safely promote weight loss are urgently needed to halt the rising prevalence of obesity and its associated complications, such as type 2 diabetes (T2D). Gut hormones are important regulators in metabolism and have therapeutic potential as treatments for obesity and T2D. The gut hormone peptide YY (PYY) is released from the intestine after a meal. Exogenous PYY3–36 suppresses food intake in both rodents and humans, including in the obese state. PYY3–36 suppresses appetite by acting on its receptor, the Y2R. Y2R is expressed in brain appetite centres but also in the afferent vagus nerve, the main neuroanatomical link carrying information from the gut to the brain. However, the relevant contribution of the afferent vagus to the overall effects of PYY3–36 is unknown. Chemogenetic activation of vagal afferent neurones results in reduced food intake (surpassing the effects of PYY) and might have altered the immune landscape of the gastrointestinal tract. To dissect the role of the Y2R expressed in the afferent vagus, we have developed a novel microsurgical technique in the mouse. Our work suggests that vagal Y2R mediates the anorectic effect of low dose and endogenous PYY3–36 and that this vagal signalling pathway regulates short-term feeding. This anorectic effect was not caused by an aversive response. In vitro calcium imaging confirmed that PYY3–36 directly activates vagal afferents. Chronic treatment of diet-induced obese (DIO) mice with a long-acting PYY3–36 analogue, Y242, did not cause a significant body weight loss. Longitudinal tracking of individual islet function using a novel imaging platform allowed to study the effect of diet and Y242 treatment. Chronic Y242 did not improve or worsen islet function in obese mice. Therefore, PYY-based treatments might not be suitable as a single agent but have potential in combination with other gut-hormones. Vagus nerve neuromodulation has shown potential as an anti-obesity therapy and the work in this thesis adds to a better understanding of vagal afferent function which will help optimise therapeutic interventions.