A good model to investigate appetite reduction in humans and rodents with associated major weight loss is bariatric surgery. Gastric bypass, but not gastric banding caused increased postprandial PYY and GLP-1 favouring enhanced satiety. An early and exaggerated insulin response mediates improved glycaemic control. The rodent model of bypass showed elevated PYY, GLP-1 and gut hypertrophy compared with sham-operated rats. Moreover, exogenous PYY reduced food intake while blockade of endogenous PYY increased food intake. A prospective follow-up human study of gastric bypass showed progressively increasing PYY, enteroglucagon, and GLP-1 responses associated with enhanced satiety. Blocking these responses in animal and human models leads to increased food intake. Thus, following gastric bypass, a pleiotrophic endocrine response may contribute to improved glycaemic control, appetite reduction, and long-term lowering of body weight. Energy expenditure in gastric bypass rats is also increased after gastric bypass surgery with major contributions coming from enhanced basal metabolic rate and diet induced thermogenesis, while no changes were noted in physical activity, body temperature or activity of brown adipose tissue. The sustained nature of weight loss and reduced appetite may be explained by gut adaptation and chronic hormone elevation.