Extreme obesity is one of the major health problems related to Prader-Willi syndrome (PWS), yet there are few effective medications. Endocannabinoids (eCBs) are lipid signaling molecules that act on a cellular receptor, called the CB1 receptor. This receptor is present in the brain and in peripheral tissues, where it also recognizes the psychoactive component of marijuana. By activating CB1 receptors, eCBs produce marijuana-like effects, including an increase in appetite (‘the munchies’) and body weight. This observation has prompted pharmaceutical companies to develop drugs that block CB1 receptors as potential treatment for obesity. One example of such a drug is rimonabant, a CB1 blocker that was proven to be effective in reducing body weight in obese/overweight people. Rimonabant also had promising effects in reducing body weight and fat mass in adults with PWS. However, its widespread use and further clinical testing was halted, because it also caused psychiatric side effects, such as depression, anxiety, and paranoia. These side effects are believed to be due to blockade of CB1 receptors located in the brain. To date, no study has tested the involvement of the peripheral eCB system (i.e. outside the brain) in the development of obesity in PWS. This is in part because CB1 antagonists that act only outside the brain were not available. We will exploit novel CB1 antagonists that do not enter the brain to examine the hypothesis that overactivation of the peripheral eCB system is responsible for the increased body weight in PWS, using a pre-clinical animal model. Our results will document the contribution of the peripheral eCB system to the metabolic phenotype associated with PWS. This research could lead to the development and clinical testing of peripherally restricted CB1 antagonists for the treatment of obesity and hyperphagia in PWS while avoiding the risk of psychiatric side effects.