Prader-Willi Syndrome (PWS) is a genetic disease characterized by failure to thrive and low muscle tone during infancy, followed by food-seeking, insatiable appetite and progressive obesity in childhood. The resulting increases in total body fat and decreases in muscle mass lead to metabolic problems such as diabetes and heart disease. Several diets are recommended for the management of body weight in individuals with PWS such as the Red-Yellow-Green system which is a low-fat, low calorie diet. However, none of the recommended diets have been scientifically proven to benefit individuals with PWS. Additionally, attempts to control weight and prevent food-seeking have variable success in PWS because the underlying basis for their food-seeking and the optimal dietary composition of nutrients such as carbohydrate, fat and protein for metabolic control in PWS remains to be determined. We propose a detailed, cutting-edge study that will assess a wide array of metabolites (“metabolomics” study) in many important metabolic pathways in PWS in response to intake of varying diets (low carbohydrate versus low fat). We will also assess measures of appetite and hunger before and after each different diet. Our previous studies have shown that the excessive food seeking in PWS may be triggered or maintained by an increase in levels of an appetite-stimulating hormone called ghrelin. We therefore propose that studies of the nutrient regulation of ghrelin will provide guidance in the design of effective diets for PWS based on scientific evidence. Information obtained from this study will be used to design evidence-based diet plans for children with PWS. Results of this study also may benefit children with other genetic obesity conditions.