Apart from genetic predisposition to obesity associated with functional polymorphisms affecting LEP and LEPR gene expression, epigenetic alterations in the transcriptional LEP gene regulation could lead to obesity by decreasing leptin secretion by adipocytes, suggesting that individuals with obesity and low leptin levels could remain sensitive to leptin and benefit from leptin therapy. The gene discussed is LEPR; the disease is obesity due to melanocortin 4 receptor deficiency.