The function of MC4R (melanocortin 4 receptor, ENSG00000166603) is as follows. G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor (PubMed:12646665, PubMed:14764818, PubMed:25163632, PubMed:32327598, PubMed:33858992, PubMed:8392067). Functions as a central component of the leptin- melanocortin pathway, which is essential for maintaining energy homeostasis (PubMed:32327598, PubMed:33858992). Upon activation, couples to G(s) protein, stimulating adenylate cyclase and the cAMP- dependent signaling pathway, which promotes anorexogenic signaling in the hypothalamus and contributes to a negative energy balance (PubMed:12588803, PubMed:14764818, PubMed:25163632, PubMed:33858992). Regulates food intake: activation by agonists suppresses appetite, whereas the antagonist Agouti-related protein/AGRP precludes agonist- induced signaling, thereby stimulating appetite (PubMed:9311920, PubMed:29311635). Modulates the firing activity of neurons in paraventricular nucleus (PVN) of the hypothalamus via alpha-MSH and AGRP regulation of inwardly rectifying potassium channel KCNJ13 closure, independently of G(s) signaling (PubMed:32327598). In the PVN, also interacts with opsin 3/OPN3, which couples to G(i/o) proteins to inhibit MC4R-mediated cAMP signaling, thereby promoting food intake (PubMed:39951488). In intestinal epithelial cells, contributes to inhibition of hepatic glucose production via nesfatin-1/NUCB2, leading to increased cAMP levels and glucagon-like peptide 1 (GLP-1) secretion (PubMed:39562740). Interaction with MGRN1 displaces the G(s) protein, further decreasing MC4R signaling activity (PubMed:19737927). Also activated by gamma-MSH, though with low potency (PubMed:8392067). {ECO:0000269|PubMed:12588803, ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:14764818, ECO:0000269|PubMed:19737927, ECO:0000269|PubMed:25163632, ECO:0000269|PubMed:29311635, ECO:0000269|PubMed:32327598, ECO:0000269|PubMed:33858992, ECO:0000269|PubMed:39562740, ECO:0000269|PubMed:39951488, ECO:0000269|PubMed:8392067, ECO:0000269|PubMed:9311920}.