Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

The individual risk for common diseases not only depends on genetic but also on epigenetic polymorphisms. To assess the role of epigenetic variations in the individual risk for obesity, we have determined the methylation status of two CpG islands at the POMC locus in obese and normal-weight children. We found a hypermethylation variant targeting individual CpGs at the intron2–exon3 boundary of the POMC gene by bisulphite sequencing that was significantly associated with obesity. POMC exon3 hypermethylation interferes with binding of the transcription enhancer P300 and reduces expression of the POMC transcript. Since intron2 contains Alu elements that are known to influence methylation in their genomic vicinity, the exon3 methylation variant seems to result from an Alu element–triggered default state of methylation boundary definition. Exon3 hypermethylation in the POMC locus represents the first identified DNA methylation variant that is associated with the individual risk for obesity. Twin studies reveal a strong genetic background of body-weight regulation. However, gene mutations in early onset obesity patients are rare. Results from large genome-wide association studies explain less than 4% of body-weight variability. Therefore, other mechanisms like epigenetic alterations may play a role in body-weight regulation. We analysed the DNA methylation of the POMC gene, which plays a central role in body-weight regulation within the hypothalamus. We observed a significant increase in the methylation score in obese children as compared to normal-weight individuals. This DNA methylation variant affects POMC gene dosage regulation. Therefore we conclude that this DNA hypermethylation variant in obese patients leads by modification of POMC gene expression to an increased individual risk for the development of obesity. This result illustrates how DNA methylation alterations increase the susceptibility to a common disease like obesity.