Melanocortinergic pathways clearly appear to be involved in obesity-associated sympathetic overactivity and its hemodynamic and thermoregulatory consequences. Individuals with dysfunctional mutations in the melanocortin-4 receptor gene (MC4R) are subject to obesity without developing hypertension.This study aimed at characterizing the impact of the MC4R on sympathetic nerve traffic relevant to the cardiovascular system in humans.Participants included eight heterozygous carriers of MC4R mutations leading to a reduced function and control subjects matched for gender, age, and body mass index.We investigated vasoconstrictive muscle sympathetic nerve activity (MSNA), a direct measure of central sympathetic nervous outflow. MSNA was recorded microneurographically from the peroneal nerve at supine rest and during apnea-induced sympathoexcitation. Sympathetic activity was correlated with serum leptin levels and hemodynamic and anthropometric data.Individuals with MC4R impairment due to functional MC4R mutations were characterized by an inverse correlation between MSNA with body mass index and leptin levels, with the most obese subjects having the lowest MSNA. Resting MSNA, diastolic blood pressure, and heart rate tended to be lower in MC4R mutation carriers, and stimulated MSNA during apnea was significantly lower as compared with control subjects.The fact that obese subjects with MC4R mutations show an inverse relationship between obesity and MSNA suggests that central sympathetic outflow to the vasculature might depend on functional melanocortinergic pathways. Their dysfunction could explain reduced sympathoexcitability, lower sympathetic nerve-induced lipolysis, and the fact that blood pressure is rarely elevated in this type of obesity.