Even a twofold increase in OBR surface expression with endospanin 1 knock-down was sufficient to significantly increase leptin-induced STAT3 phosphorylation in vitro and in vivo in the ARC of the hypothalamus, and was efficient in preventing or reversing the development of obesity in mice fed with a high-fat diet (133, 139). This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.