Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 13, Issue 590, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abd6434
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Funding
- NIH [DK070332, DK126715, F32HD095620, K99DK127065, DK106476, F32DK123879]
- Common Fund of the Office of the Director of the NIH
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
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Research has shown that MC3R plays a crucial role in controlling feeding behavior, primarily through its impact on the AgRP circuitry. While there is sexual dimorphism in the expression of MC3R in different brain regions, there is no sexual dimorphism in AgRP neurons. MC3R is considered a potential therapeutic target for disorders such as anorexia.
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.
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