INS and obesity due to melanocortin 4 receptor deficiency: Up to present, it has been reported that 0.046% of peripheral insulin penetrates BBB [10], that insulin receptor (IR) is expressed in the brain [11], and that neuron-specific deletion of IRs in the brain alters fuel metabolism, reproduction, and hepatic glucose production [11] as well as inducing diet-sensitive obesity and female-selective hyperphagia [12].