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

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.

MC3R links nutritional state to childhood growth and the timing of puberty

“…In contrast, our homozygous null proband has been obese since early childhood, with no evidence for mutations in known obesity genes. MC3R is expressed on both POMC and AgRP neurons and could influence their function in controlling energy balance 39 . Resolution of this question will require the identification of additional humans homozygous for LoF MC3R mutations.…”

“…Using a single-cell RNA sequencing dataset of the arcuate nucleus (ARC) 38 Sweeney et al 39 recently reported that Mc3r expression was significantly enriched in neurons expressing Kisspeptin, Neurokinin B and Dynorphin (so called KNDy neurons) and in Growth Hormone-releasing Hormone (GHRH) neurons. We undertook an expanded analysis including three additional studies [40][41][42] S12).…”

The Role of Leptin in the Development of Energy Homeostatic Systems and the Maintenance of Body Weight

“…POMC is posttranslationally cleaved by proconvertases (PC1 and PC2) and other peptidases to create several smaller peptides including β-endorphin and α-melanocyte stimulating hormone (α-MSH) (Benjannet et al, 1991). α-MSH inhibits energy intake and stimulates energy expenditure via melanocortin 4 receptors (MC4R) and, to a lesser degree, melanocortin 3 receptors (MC3R) located on second order neurons (Seeley et al, 1997;Sweeney et al, 2021). AgRP is an antagonist of MC4R (Ollmann et al, 1997) and opposes the effects of POMC.…”

Metabolic Profiling of Mice with Deletion of the Orphan G Protein-Coupled Receptor, GPR37L1

“…We elected to use male mice because it is well established that male C57BL/6J mice are much more susceptible than females to dyslipidaemia, weight gain and glucose intolerance in response to high-fat diets [ 46 , 54 , 55 , 56 ]. Furthermore, the magnitude of knockout genotype effects in females in metabolic phenotyping studies is often much lower than in their male counterparts [ 57 , 58 , 59 , 60 ]. If a scientifically or clinically valuable phenotype had emerged in this study, follow-up experiments with female mice would be justified.…”