Leptin resistance has been suggested to be the major culprit for obesity development in both obese patients and DIO in rodents.6,16,31 In this context, it is generally assumed that strategies to reverse leptin resistance will be able to reduce obesity.6,16 Thus, extensive efforts have been devoted to understanding the underlying mechanism responsible for leptin resistance, which remains elusive. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.