We sought to delineate the physiological significance of MRAP2 in MC4R neurons, with a particular focus on metabolic, autonomic and cardiovascular functions.<h4>Methods and results</h4>Selective deletion of MRAP2 in MC4R neurons causes obesity that was associated with hyperphagia and impairment in glucose homeostasis and insulin sensitivity. The gene discussed is MC4R; the disease is obesity due to melanocortin 4 receptor deficiency.