Research ArticleEATING DISORDERS

The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia

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Science Translational Medicine  21 Apr 2021:
Vol. 13, Issue 590, eabd6434
DOI: 10.1126/scitranslmed.abd6434

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An agonist against anorexia

The eating disorder anorexia nervosa is potentially fatal but also poorly understood. Sweeney et al. now show that AgRP (Agouti-related protein)–expressing neurons, previously linked to anorexic feeding behavior, regulate food intake via the melanocortin-3 receptor (MC3R). Chemogenetic and pharmacological approaches to control the MC3R in AgRP neurons bidrectionally altered feeding and anxiety-like behavior in male and female mice, with an MC3R antagonist and agonist promoting weight loss and gain, respectively. This study provides proof of principle for pharmacologically targeting MC3R in AgRP neurons to alter food intake.

Abstract

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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