Abstract Aims The melanocortin receptor accessory protein 2 (MRAP2), which is abundantly expressed in the brain including the hypothalamus, has emerged as a key regulator of melanocortin-4 receptor (MC4R) activity. We sought to delineate the physiological significance of MRAP2 in MC4R neurons, with a particular focus on metabolic, autonomic and cardiovascular functions. Methods and results Selective deletion of MRAP2 in MC4R neurons causes obesity that was associated with hyperphagia and impairment in glucose homeostasis and insulin sensitivity. MC4R agonist Melatonan II (MTII)-induced anorectic effects were blunted in mice lacking MRAP2 in MC4R neurons, whereas Celastrol retained its efficacy in reducing food intake and body weight. MRAP2 deletion also reduced baseline sympathetic nerve activity (SNA), particularly the SNA subserving the kidney. This was associated with reduced innervation of the kidney. In addition, MTII-induced increases in renal and brown adipose tissue (BAT) SNA as well as hepatic vagal nerve activity were significantly attenuated in MC4R neuron MRAP2-deficient mice. Transynaptic tracing revealed that MC4R neurons projecting to BAT and kidneys were localized to specific brain nuclei including the paraventricular nucleus of the hypothalamus, providing anatomical substrate for MRAP2 regulation of sympathetic outflow. Although the loss of MRAP2 in MC4R neurons did not affect arterial pressure, it caused a significant decrease in heart rate and baroreflex sensitivity. Finally, MRAP2 deficiency in MC4R neurons attenuated MTII-induced increase in arterial pressure and heart rate. Conclusion These findings demonstrate that in addition to its role in energy balance and glucose homeostasis MRAP2 in MC4R neurons is crucial for cardiovascular autonomic regulation and is required for the development of obesity-associated hypertension and autonomic dysfunction.