The brain balances energy stores with energy expenditure with little conscious effort. The hypothalamus is a part of the brain that senses levels of a hormone called leptin, which is produced by fat. Excess leptin normally causes a decrease in appetite and increase in activity. This balance is disrupted in obese children who carry mutations in genes in the leptin response pathway. We now have convincing evidence that one of the genes inactivated in children with PWS, namely MAGEL2, is essential for leptin signaling in the hypothalamus. Mice missing Magel2 are obese and underactive. We found that some of the hypothalamus cells that sense leptin do not properly function in mice missing Magel2. These neurons normally act on other neurons through the release of a factor called alpha-MSH. We believe this defect causes the mice to fail to properly balance their food intake and activity levels, leading to obesity. We propose that loss of human MAGEL2 causes the fat accumulation, reduced resting energy expenditure, and contributes to hyperphagia in children with PWS. Thus, the underlying cause of obesity in PWS may have considerable overlap with other genetic disorders that cause severe childhood obesity. In this study, we will examine whether mice lacking Magel2 are unresponsive to leptin from birth, or whether insensitivity happens gradually. We will test whether giving the Magel2 mutant mice a drug that is similar to the missing alpha-MSH causes them to eat less and lose weight. We will also test whether daily administration of this drug prevents the Magel2 mice from becoming obese. In summary, these experiments will determine the best time for interventions that improve sensing of leptin in neonatal and juvenile mice, and test a potential treatment for leptin insensitivity, using an obese mouse model of PWS.