The melanocortin pathway and energy homeostasis: From discovery to obesity therapy.
Mol Metab
; 48: 101206, 2021 06.
Article
en En
| MEDLINE
| ID: mdl-33684608
ABSTRACT
BACKGROUND:
Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. SCOPE OF REVIEW Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target. MAJORCONCLUSIONS:
Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Alfa-MSH
/
Transducción de Señal
/
Fármacos Antiobesidad
/
Receptor de Melanocortina Tipo 4
/
Metabolismo Energético
/
Melanocortinas
/
Homeostasis
/
Obesidad
Límite:
Animals
/
Humans
País/Región como asunto:
America do norte
Idioma:
En
Revista:
Mol Metab
Año:
2021
Tipo del documento:
Article