Targeting the central melanocortin system for the treatment of metabolic disorders

This article discusses the neuroanatomy and function of the central melanocortin circuitry, focusing on metabolic disorders. Progress and limitations of therapeutics targeting this system and potential strategies to improve melanocortin-based therapeutics are outlined. A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.

Automated summary

This article discusses the neuroanatomy and function of the central melanocortin circuitry, focusing on metabolic disorders. Progress and limitations of therapeutics targeting this system and potential strategies to improve melanocortin-based therapeutics are outlined. A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders. The recent FDA approvals of drugs targeting melanocortin receptors have demonstrated the safety and renewed excitement in the development of melanocortin-based therapeutics.