Particularly, they have shown that while the restoration of MC4Rs in Sim1 neurons in the PVN dramatically reduced obesity of Mc4r-null mice, selective disruption of glutamate release from these MC4R neurons prevented this reversal effect by affecting both energy expenditure and food intake, further indicating that glutamate mediates the function of MC4Rs on PVN Sim1 neurons in thermoregulation as well as feeding control (87). This evidence concerns the gene SIM1 and obesity due to melanocortin 4 receptor deficiency.