We tested the hypothesis that abolishing vagal nerve activity will reverse the obesity phenotype of melanocortin 4 receptor knockout mice (). In two separate studies, we examined the efficacy of bilateral subdiaphragmatic vagotomy (SDV) with pyloroplasty in the prevention and treatment of obesity in mice. In the first study, SDV prevented >20% increase in body weight (BW) associated with this genotype. This was correlated with a transient reduction in overall food intake (FI) in the preventative arm of the study. Initially, SDV mice had reduced weekly FI; however, FI normalized to that of controls and baseline FI within the 8-week study period. In the second study, the severe obesity that is characteristic of the adult genotype was significantly improved by SDV with a magnitude of 30% loss in excess BW over a 4-week period. Consistent with the first preventative study, within the treatment arm, SDV mice also demonstrated a transient reduction in FI relative to control and baseline levels that normalized over subsequent weeks. In addition to the accompanying loss in weight, mice subjected to SDV showed a decrease in respiratory exchange ratio (RER), and an increase in locomotor activity (LA). Analysis of the white fat-pad deposits of these mice showed that they were significantly less than the control groups. Altogether, our data demonstrates that SDV both prevents gain in BW and causes weight loss in severely obese mice. Moreover, it suggests that an important aspect of weight reduction for this type of monogenic obesity involves loss of signaling in vagal motor neurons.