The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have therefore developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The brainstem and hypothalamus serve as key homeostatic sites receiving and integrating the neural, nutrient, and hormonal signals that convey nutritional status and orchestrating appropriate efferent responses. Energy homeostasis is controlled by long-term adiposity hormones, such as leptin and insulin, which reflect overall energy stores and short-term gastrointestinal signals that convey information pertaining to individual meals. Gut hormones released postprandially in a nutrient-dependent manner include cholecystokinin, glucagon-like peptide 1, peptide YY, oxyntomodulin and pancreatic polypeptide. All of these hormones have been shown to reduce food intake when administered peripherally to rodents or humans. In contrast, ghrelin produced primarily in the stomach, has been shown to stimulate food intake. These hormones have been shown to act via both brainstem and more recently hypothalamic arcuate nucleus pathways to modulate behavioural, autonomic and neuroendocrine responses to food intake. Studies in obese rodent models and in human subjects have started to reveal abnormalities in these gut hormone mechanisms in obesity. The gut hormone peptide3-36 (PYY) is released in response to ingestion of nutrients and in proportion to the calories ingested. In lean, normal-weight and obese human volunteers venous infusion of PYY reduces hunger and food intake. The precise mechanism by which PYY exerts its anorectic effects remains to be determined and evidence exists for hypothalamic, brainstem and vagal sites of action. However, mechanistic data from rodents has confirmed that PYY mediates its anorectic actions via the NPY Y2 receptor. Obese adults and children have been reported to have low circulating plasma concentrations of PYY, whilst increased levels have been reported in patients with anorexia nervosa. These findings suggest that PYY plays a role in the regulation of body weight and that PYY defiency might be involved in the pathogeneis of obesity. To test this hypothesis we genereated transgenic mice that lacked PYY. We found that from weaning PYY-null mice were hyperphagic and obese and that their obese phenotype was reversible with exogenous PYY treatment. Chronic peripheral administration of PYY to rodents with diet-induced obesity also reduces food intake and adiposity. Increased protein diets have been shown to reduce hunger, increase satiety and cause greater weight loss than normal-protein diets. Recently, we have shown that high-protein diets cause the greatest satiety and release of PYY compared with high-fat or high-carbohydrate diets. Moreover, we found that PYY was critical for the beneificial effects of high-protein diets. Post-bariatric surgery PYY levels are markedly increased and part of the weight loss effects of this procedure have been attributed to increased PYY. Taken together these findings suggest that increasing PYY plasma concentration either by exogenous administration or by stimulating endogenous PYY release may offer an effective treatment for obesity.