The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
21 04 2021
21 04 2021
Historique:
received:
02
07
2020
revised:
19
11
2020
accepted:
25
03
2021
entrez:
22
4
2021
pubmed:
23
4
2021
medline:
13
7
2021
Statut:
ppublish
Résumé
Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.
Identifiants
pubmed: 33883274
pii: 13/590/eabd6434
doi: 10.1126/scitranslmed.abd6434
pmc: PMC9022017
mid: NIHMS1795864
pii:
doi:
Substances chimiques
Receptor, Melanocortin, Type 3
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK070332
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK126715
Pays : United States
Organisme : NIDDK NIH HHS
ID : K99 DK127065
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK123879
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK106476
Pays : United States
Organisme : NICHD NIH HHS
ID : F32 HD095620
Pays : United States
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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