Treatment options for obesity and type 2 diabetes include efforts to avoid the original weight gain: reducing energy input either by life-style changes or pharmacological manipulation. However, success is proving difficult, and it is therefore important to provide a better understanding of how other aspects of energy regulation might prevent the development of metabolic disease. We and others working on satiety signalling have gone some way to understanding brain communication with the gut to control meal size. However, it is equally important to regulate other aspects of energy homeostasis through central regulation of other peripheral organs. For example, clinical interest has highlighted the importance of post-prandial regulation of hepatic gluconeogenesis to avoid development of diabetes, and the potential for brown adipose-dependent thermogenesis in adult humans to avoid obesity. We will discuss animal models we are using to elucidate the role of RFamide peptides in satiety, thermogenesis and glucose tolerance. The RFamides are so called because they all have common C-terminal arginine and phenylalanine residues. Through evolution, from nematodes and gastropods to birds and mammals, the RFamides have had a role in feeding behaviour. In rodents, brainstem neurones containing the RFamide, prolactin-releasing peptide (PrRP), mediate the effects of the gut-brain-gut satiety signal, cholecystokinin. Thus, PrRP can mimic satiation and the reduction in gastric emptying, whilst the actions of cholecystokinin are absent in mice lacking either PrRP or its receptor (GPR10). More recently, cholecystokinin has been shown to help protect against post-prandial hyperglycaemia by activating a gut-brain-liver reflex which reduces hepatic glucose production. Although GPR10 knock-out mice have normal fasting glucose levels, they demonstrate a large excursion in blood glucose following oral gavage (2 g glucose/kg body weight; glucometer measurements from tail vein blood samples). Conversely, pre-administration of PrRP (4 nmol; icv) into normal mice reduces the glucose excursion during a similar oral glucose tolerance test. We have demonstrated also that PrRP neurones in the hypothalamus, are responsible for brown adipose tissue-mediated, non-shivering thermogenesis in response to either leptin (6 mg/kg; ip) or an acute cold stimulus (4oC for 2 hours). The GPR10 knock-out mouse is obese. Agonistic targeting of the “catabolic peptide” PrRP and its receptor may provide a route to controlling different aspects of metabolic dysfunction. By contrast, another RFamide, QRFP, is anabolic and has many opposing effects to PrRP. Therefore, it may be open to antagonistic targeting. For example, QRFP (2 nmol; icv) increases food intake, reduces glucose tolerance and increases lipogenesis. Perhaps unexpectedly, the peptide does not have an obvious direct effect on energy expenditure. The role of QRFP on feeding appears to be a central action, while its other effects may be mediated through peripheral tissues.