The adipose tissue-derived hormone leptin plays a critical role in whole body energy homeostasis: lack of functional leptin or leptin receptors (Lepr) results in severe and early onset obesity in rodents and humans, while leptin replacement in leptin-deficient rodents and humans fully recovers energy homeostasis1,2. The gene discussed is LEPR; the disease is obesity due to melanocortin 4 receptor deficiency.