Williams, S. Y. | bioRxiv Science

bioRxiv2023

Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents

The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to other agents, including the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor, leptin, demonstrated that increased sensitivity to anorectic agents is a generalized result of MC3R antagonism. Enhanced neuronal activation in multiple nuclei, including ARH, VMH, and DMH, was observed using Fos immunohistochemistry following low-dose liraglutide in MC3R knockout mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits regulating multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r -/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1R analogs, suggesting that MC3R antagonists may have value in enhancing the dose-response range of obesity therapeutics.

neuroscience↗

bioRxiv2022

Demonstration of a common DPhe7 to DNal(2')7 peptide ligand antagonist switch for the melanocortin-3 and melanocortin-4 receptors identifies systematic mischaracterization of the pharmacological properties of melanocortin peptides

Melanocortin peptides containing a D-naphthylalanine residue in position 7 (DNal(2)7), reported as melanocortin-3 receptor (MC3R) subtype-specific agonists in two separate publications, were found to lack significant MC3R agonist activity. The cell lines used at the University of Arizona for pharmacological characterization of these peptides, consisting of HEK293 cells stably transfected with human melanocortin receptor subtypes MC1R, MC3R, MC4R, or MC5R, were then obtained and characterized by quantitative PCR. While the MC1R cell line correctly expressed only the hMCR1, the three other cell lines were mischaracterized with regard to receptor subtype expression. Demonstration that a D-naphthylalanine residue in position 7, irrespective of the melanocortin peptide template, results primarily in antagonism of the MC3R and MC4R, then allowed us to search the published literature for additional errors. The erroneously characterized DNal(2)7-containing peptides date back to 2003; thus, our analysis suggests that systematic mischaracterization of the pharmacological properties of melanocortin peptides occurred.

pharmacology and toxicology↗