TY - JOUR
T1 - The melanocortin pathway and energy homeostasis
T2 - From discovery to obesity therapy
AU - Yeo, Giles S.H.
AU - Chao, Daniela Herrera Moro
AU - Siegert, Anna Maria
AU - Koerperich, Zoe M.
AU - Ericson, Mark D.
AU - Simonds, Stephanie E.
AU - Larson, Courtney M.
AU - Luquet, Serge
AU - Clarke, Iain
AU - Sharma, Shubh
AU - Clément, Karine
AU - Cowley, Michael A.
AU - Haskell-Luevano, Carrie
AU - Van Der Ploeg, Lex
AU - Adan, Roger A.H.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/6
Y1 - 2021/6
N2 - 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. Major conclusions: 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.
AB - 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. Major conclusions: 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.
KW - Genetics
KW - Hypothalamus
KW - Melanocortin
KW - Obesity
KW - Pharmacology
KW - Therapy
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U2 - 10.1016/j.molmet.2021.101206
DO - 10.1016/j.molmet.2021.101206
M3 - Review article
C2 - 33684608
AN - SCOPUS:85103627439
SN - 2212-8778
VL - 48
JO - Molecular Metabolism
JF - Molecular Metabolism
M1 - 101206
ER -