Plasma levels of the peptide hormone ghrelin are markedly elevated in individuals with Prader-Willi Syndrome (PWS), however the functional consequences of this elevation have not yet been determined, nor are the mechanistic causes of ghrelin elevation known. Many attribute the characteristic, maladaptive PWS eating behaviors directly to ghrelin, based mainly on ghrelin’s potent eating-stimulatory actions in non-PWS mouse models. Ghrelin’s abilities to promote growth hormone secretion, regulate blood glucose levels, and lower depression and anxiety may impact others of PWS’s characteristic features. Our overall goal in this proposal is to determine the “Why” of ghrelin elevation in PWS. In particular, we will determine if the elevated ghrelin observed in PWS is beneficial, detrimental, or inconsequential. We hypothesize that ghrelin plays a protective role in PWS – especially as it regards growth hormone deficiency-associated processes, hypoglycemia and mental health issues, while also being detrimental as it regards the extreme food-seeking behaviors and obesity. Whatever its role, individuals with PWS deserve a full vetting of the impact of ghrelin on their condition. Using genetically engineered mice, our custom mouse food reward behavioral models, and our expertise in ghrelin action, ghrelin secretion, metabolism and mouse behavior, we plan to systematically probe the metabolic, growth and behavioral effects of elevated plasma ghrelin in PWS. Novel facets of this application include the use of recombinant DNA technology to disrupt the ghrelin system in a PWS mouse model, the concept that ghrelin has protective effects in PWS, and the inclusion of formal evaluations of complex, reward-based eating behavior in PWS mouse models. Should our overall hypothesis prove untrue, we can proceed with other avenues of research to find treatments for the many debilitating features of PWS. If our overall proposed hypothesis is proved, we will use these data for future translational studies that selectively target the ghrelin system in individuals with PWS. Either outcome should have a significant impact on the PWS community.