Since less than 1% of peripheral insulin is taken up by the brain22 via a saturable receptor-mediated process23,24 and proinsulin has a 100-fold reduced affinity for the insulin receptor25, it is conceivable that impaired proinsulin processing could lead to reduced central insulin action and thus hyperphagic obesity. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.