Affinage

MC4R

Melanocortin receptor 4 · UniProt P32245

Length
332 aa
Mass
36.9 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC4R is a hypothalamic G-protein-coupled receptor that integrates multiple, mechanistically distinct signaling modalities to control energy homeostasis, feeding, glucose metabolism, and autonomic outflow (PMID:31002796, PMID:34823066). Beyond canonical Gαs/cAMP coupling, MC4R signals through Gq/11α, which is specifically required for the acute suppression of food intake (PMID:38175730), through β-arrestin recruitment whose maximal efficacy explains the bulk of BMI variance among human MC4R variants and underlies obesity-protective signaling bias (PMID:31002796), and G-protein-independently through inwardly rectifying potassium channels, closing Kir7.1 in response to α-MSH while AgRP acts as a biased agonist that opens it (PMID:25600267). The agonist α-MSH and the endogenous hormone LCN2 drive anorexigenic signaling, while AgRP functions as both inverse agonist and antagonist (PMID:28273060, PMID:28512117). MC4R localizes to and functions at neuronal primary cilia, a step requiring the accessory protein MRAP2; constitutive receptor activity drives continuous ciliary exit via β-arrestin, ubiquitination, and the BBSome, whereas AgRP-mediated inhibition causes ciliary accumulation (PMID:36692018, PMID:39899600). MRAP2 additionally modulates ligand sensitivity and multiple downstream pathways, and human MRAP2 variants that impair this modulation are obesity-associated (PMID:39807633, PMID:28512117). Most obesity-causing MC4R mutations act by impairing plasma-membrane trafficking through misfolding or ubiquitin-mediated ER retention, defects rescuable by pharmacological or chemical chaperones, while gain-of-function variants bias signaling toward β-arrestin (PMID:31002796, PMID:20826565, PMID:23251400). Downstream, anatomically distinct MC4R neuronal populations in the PVN, LHA, and ARC control sympathetic outflow to brown adipose tissue and kidney, thereby governing thermogenesis, glucose tolerance, renal glucose reabsorption, and counterregulatory responses to hypoglycemia (PMID:25605803, PMID:33052459, PMID:34823066, PMID:30503832). Loss-of-function MC4R mutations cause human hyperphagic obesity with impaired satiety (PMID:31670905).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 Medium

    Established that the dominant pathogenic mechanism for obesity-associated MC4R variants is impaired cell-surface trafficking rather than pure signaling loss, reframing MC4R obesity as a receptor-localization disease.

    Evidence Flow cytometry surface-expression and cAMP-luciferase assays across 50 obesity-associated mutations with structural modeling

    PMID:12851297

    Open questions at the time
    • Did not distinguish misfolding from other retention mechanisms
    • No in vivo confirmation of trafficking defect
    • Constitutive-activity-impaired class left mechanistically undefined
  2. 2010 Medium

    Placed SIM1 transcriptionally upstream of MC4R and showed pharmacological chaperones can rescue mistrafficked mutants, defining a transcriptional input and a therapeutic strategy for retention defects.

    Evidence Conditional Sim1 knockout with Mc4r mRNA quantification; surface-expression and cAMP assays of 10 mutants with 5 chaperones

    PMID:20220015 PMID:20826565

    Open questions at the time
    • SIM1-MC4R link is mRNA-level, not direct chromatin regulation
    • Chaperone efficacy is mutation-specific and incompletely predictable
    • No in vivo chaperone rescue at this stage
  3. 2012 Medium

    Distinguished ubiquitin-mediated ER retention from misfolding by showing the P272L mutant is retained via ubiquitination and rescued by E1 inhibition but not chemical chaperones, refining the trafficking-defect taxonomy.

    Evidence Confocal ER localization, surface expression, cAMP assays, and ubiquitination assays with UBE-41 versus PBA treatment

    PMID:23251400

    Open questions at the time
    • Single mutant analyzed
    • E3 ligase responsible not identified
    • Relevance to neuronal context untested
  4. 2015 High

    Revealed G-protein-independent and temporally/compartmentally selective MC4R signaling: coupling to Kir7.1 with AgRP as a biased channel-opening agonist, and persistent compartmentalized cAMP signaling distinct from α-MSH.

    Evidence Patch-clamp electrophysiology in mouse PVN neurons with Gαs-deficient models; FRET-based temporal cAMP and FRAP in neuronal cell lines

    PMID:25600267 PMID:26418335

    Open questions at the time
    • Molecular basis of MC4R-Kir7.1 coupling not resolved
    • Persistent signaling compartment not definitively identified in vivo
  5. 2015 High

    Dissociated MC4R's metabolic functions from body weight by showing LHA MC4R controls sympathetic outflow to brown fat and glucose tolerance independently of weight.

    Evidence Site-specific viral MC4R rescue in null mice, multifiber sympathetic nerve recording, FDG-PET, and iBAT denervation

    PMID:25605803

    Open questions at the time
    • Downstream effectors in iBAT beyond GLUT4 unresolved
    • Neuronal subtype within LHA not defined
  6. 2017 High

    Identified LCN2 as a peripheral hormone agonist acting on hypothalamic MC4R and established MRAP2 as a conserved accessory protein modulating MC4R ligand sensitivity and constitutive activity, broadening the input layer to the receptor.

    Evidence Binding assays and MC4R-null epistasis for LCN2; Co-IP and CRE-luciferase reporter assays for MRAP2 in avian orthologs

    PMID:28273060 PMID:28512117

    Open questions at the time
    • LCN2 binding site on MC4R not mapped
    • MRAP2 mechanism characterized in non-mammalian ortholog at this stage
    • Setmelanotide pharmacology contrasts with α-MSH
  7. 2019 High

    Showed that β-arrestin recruitment efficacy, not Gαs/cAMP, explains the majority of BMI variance across human MC4R variants and that β-arrestin-biased gain-of-function variants protect against obesity, redefining which signaling axis is physiologically decisive.

    Evidence Functional characterization of 61 variants across cAMP, β-arrestin, and ERK assays integrated with UK Biobank population genetics

    PMID:31002796

    Open questions at the time
    • Mechanistic link between β-arrestin/MAPK signaling and downstream neuronal output unresolved
    • Does not address ciliary or Gq contributions to variant phenotypes
  8. 2019 Medium

    Identified C2CD5 as a regulator of MC4R endocytosis, linking receptor internalization control to obesity through a defined accessory protein.

    Evidence Antibody-feeding endocytosis assay in neuronal cells and C2CD5 knockout mouse metabolic phenotyping

    PMID:31666192

    Open questions at the time
    • Direct C2CD5-MC4R interaction not demonstrated
    • Endocytic adaptor mechanism incompletely defined
  9. 2020 High

    Established Gq/11α signaling as specifically required for MC4R's acute anorectic action, separating it from chronic Gαs functions and defining a discrete pathogenic class of variants.

    Evidence MC4R F51L knock-in mice with cAMP/IP1 assays and stereotaxic Gq/11α inhibitor delivery to the PVN with food intake readouts

    PMID:38175730

    Open questions at the time
    • Downstream Gq effectors in PVN neurons unresolved
    • Relationship between Gq and Kir7.1 coupling not addressed
  10. 2020 Medium

    Extended MC4R autonomic control to the kidney and counterregulatory hormone secretion, showing PVH MC4R governs renal glucose reabsorption via adrenaline/GLUT2 and hypoglycemia responses, and that human MRAP2 variants impair MC4R multi-pathway signaling.

    Evidence Region-specific MC4R knockouts with sympathetic nerve recording and adrenaline-deficient epistasis; hyperinsulinemic-hypoglycemic clamps; MRAP2 variant signaling assays with structural modeling

    PMID:30503832 PMID:33052459 PMID:39807633

    Open questions at the time
    • MRAP2-MC4R transmembrane contacts predicted by modeling only
    • Causal neuron-to-organ wiring for renal control incomplete
  11. 2021 Medium

    Defined the PVN MC4R circuit anatomy and demonstrated homodimerization and recycling/internalization as additional trafficking-level determinants of obesity-variant phenotypes.

    Evidence Viral circuit tracing with chemogenetics and physiological telemetry; flow cytometry, Co-IP, internalization and β-arrestin assays across 61 mutations

    PMID:33761344 PMID:34823066

    Open questions at the time
    • Functional role of dimerization in signaling not resolved
    • Circuit data from single lab without genetic cell-type dissection of each projection
  12. 2021 Medium

    Identified transcriptional and contextual modulators of MC4R neuronal output, including ERα recruitment to the Mc4r gene driving physical activity and endocannabinoid 2-AG gating of MC4R neuron responsiveness, and an opposing MC4R-OPRM1 axis in nociception.

    Evidence ERα ChIP at Mc4r with chemogenetics; DAGLα conditional deletion in MC4R neurons with electrophysiology; Mc1r/MC4R genetic models with PAG pharmacology

    PMID:33811065 PMID:34646010 PMID:34654741

    Open questions at the time
    • Generalizability of ERα regulation beyond VMHvl females unclear
    • Mechanism by which 2-AG alters MC4R ligand responsiveness undefined
  13. 2023 High

    Localized functional MC4R to neuronal primary cilia and identified MRAP2 as required for ciliary targeting, establishing the cilium as the compartment for long-term energy homeostasis signaling.

    Evidence MRAP2 conditional knockout mice with confocal imaging of ciliary MC4R and in vivo energy balance

    PMID:36692018

    Open questions at the time
    • Molecular mechanism of MRAP2-dependent ciliary import unresolved
    • Signaling output specific to the ciliary pool not isolated
  14. 2024 Medium

    Resolved activity-dependent regulation of ciliary MC4R, showing constitutive activity drives exit via β-arrestin/ubiquitination/BBSome while AgRP promotes accumulation, and added Kir2.1 as a direct MC4R partner in ARC POMC neurons regulating energy expenditure.

    Evidence Live-cell ciliary imaging with pharmacologic/genetic activity manipulation, ubiquitination assays, BBSome knockouts; Co-IP and Kir2.1 knockdown rescue in conditional KO mice

    PMID:38448811 PMID:39899600

    Open questions at the time
    • E3 ligase mediating ciliary-exit ubiquitination not identified
    • Kir2.1 interaction shown by single Co-IP without reciprocal structural validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct signaling modalities (Gαs, Gq/11, β-arrestin, Kir channels) are spatially partitioned between plasma membrane, endosomes, and cilia, and how this partitioning is decoded into specific physiological outputs, remains unresolved.
  • No unified model linking compartment to signaling axis to phenotype
  • Direct structural basis of MC4R-channel and MC4R-MRAP2 coupling lacking
  • Endogenous ligand occupancy at cilia versus membrane not quantified in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005929 cilium 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3
Partners
AGRPC2CD5ESR1KCNJ13KCNJ2LCN2MRAP2
Complex memberships
BBSomeMC4R homodimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 MC4R couples to inwardly rectifying potassium channel Kir7.1 in paraventricular nucleus neurons independently of Gαs signaling. α-MSH induces closure of Kir7.1 via MC4R, while AgRP acts as a biased agonist that opens Kir7.1 (hyperpolarizing neurons) independently of its inhibition of α-MSH binding, demonstrating G-protein-independent ion channel coupling. Electrophysiology in mouse PVN neurons, patch-clamp recordings, genetic mouse models with Gαs-deficient MC4R neurons Nature High 25600267
2019 The maximal efficacy of β-arrestin recruitment to MC4R, rather than canonical Gαs-mediated cAMP production, explains 88% of the variance in BMI association of MC4R variants in humans. Gain-of-function MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased MAPK pathway activation are associated with lower BMI and protection against obesity. Functional characterization of 61 MC4R variants (cAMP assay, β-arrestin recruitment assay, ERK/MAPK signaling assay) combined with population genetics in 500,000 UK Biobank individuals Cell High 31002796
2017 Lipocalin 2 (LCN2), an osteoblast-derived hormone, crosses the blood-brain barrier and binds MC4R in paraventricular and ventromedial hypothalamic neurons to activate an MC4R-dependent anorexigenic pathway, suppressing appetite. Molecular binding assays, loss- and gain-of-function mouse models, LCN2 administration with MC4R-null controls Nature High 28273060
2023 MRAP2 is required for ciliary localization of MC4R in hypothalamic neurons. MC4R localizes and functions at neuronal primary cilia, and disruption of this ciliary targeting abolishes long-term energy homeostasis control. MRAP2 acts as a specific accessory protein required for GPCR targeting to primary cilia. Genetic mouse models (MRAP2 conditional knockout), immunofluorescence/confocal imaging of MC4R ciliary localization, in vivo energy balance measurements JCI insight High 36692018
2025 MC4R's constitutive activity drives its continuous exit from neuronal primary cilia via β-arrestin, ubiquitination, and the BBSome complex. AgRP, by inhibiting MC4R activity, causes robust accumulation of MC4R in cilia. MRAP2 mediates ciliary targeting of MC4R. Live-cell imaging of MC4R ciliary levels, pharmacological and genetic manipulation of MC4R activity, ubiquitination assays, BBSome genetic knockouts PLoS biology High 39899600
2021 MC4R undergoes homodimerization, and multiple obesity-associated mutations disrupt this dimerization. Obesity-protecting mutations accelerate recycling to the plasma membrane or decrease internalization, while obesity-associated mutations primarily impair trafficking to the plasma membrane. Mutations that do not affect canonical Gαs signaling but disrupt agonist-induced internalization, β-arrestin recruitment, or Gαs coupling are nonetheless pathogenic. Flow cytometry, co-immunoprecipitation, internalization assays, β-arrestin recruitment assays, cAMP assays, structural mapping using 61 human MC4R mutations Cell reports High 33761344
2021 Oestrogen increases MC4R signaling in VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene, driving physical activity in female mice. Chemogenetic stimulation of VMHvl neurons co-expressing MC4R and ERα reverses sedentary behavior and obesity in oestrogen-depleted mice. CRISPR-mediated transcriptional activation, chemogenetics (DREADD), ERα ChIP at Mc4r locus, conditional mouse genetics, energy expenditure measurements Nature High 34646010
2010 Postnatal Sim1 deficiency in mice causes decreased hypothalamic MC4R mRNA in the PVN and hyperphagic obesity. Sim1 is required postdevelopmentally for MC4R expression in PVN neurons, placing SIM1 upstream of MC4R in the leptin-melanocortin-oxytocin pathway. Conditional Sim1 knockout using CaMKII-Cre, qRT-PCR for Mc4r mRNA, stereological cell counting, retrograde tract tracing The Journal of neuroscience Medium 20220015
2015 MC4R signaling in the lateral hypothalamic area (LHA) regulates glucose tolerance and sympathetic nerve activity to brown adipose tissue (iBAT) independently of effects on body weight. Restoring MC4R expression specifically in LHA increased sympathetic traffic to iBAT, elevated GLUT4 expression in iBAT, and improved glucose tolerance; bilateral iBAT denervation abolished this effect. Site-specific viral MC4R rescue in MC4R-null mice, multifiber sympathetic nerve recording, FDG-PET glucose uptake tracing, surgical iBAT denervation Diabetes High 25605803
2020 Hypothalamic MC4R (specifically in the paraventricular nucleus, PVH) regulates glucose reabsorption via adrenaline-mediated control of renal GLUT2. MC4R deficiency suppresses renal sympathetic nerve activity, reduces circulating adrenaline and renal GLUT2 levels, causing elevated glucosuria. Adrenaline restoration reverses the phenotype, placing adrenaline and renal GLUT2 downstream of hypothalamic MC4R. Region-specific MC4R knockout mice, renal sympathetic nerve recording, adrenaline-deficient mouse model, graded [13C6]glucose infusion for renal glucose reabsorption, Western blotting for GLUT2 Diabetologia High 33052459
2021 Endocannabinoid 2-arachidonoylglycerol (2-AG) regulates the activity of MC4R-expressing PVN neurons via inhibition of afferent GABAergic drive. Impaired 2-AG synthesis within MC4R neurons causes hypophagia and resistance to diet-induced obesity. MC4R agonist insensitivity in 2-AG-deficient MC4R neurons demonstrates that eCB signaling modulates MC4R responsiveness to its natural ligands. Conditional genetic deletion of 2-AG synthesis (DAGLα) in MC4R neurons, electrophysiology, chemogenetics, metabolic phenotyping Proceedings of the National Academy of Sciences of the United States of America Medium 34654741
2018 Setmelanotide, a potent MC4R agonist, uniquely activates NFAT (nuclear factor of activated T cells) signaling downstream of MC4R and can restore function of selected MC4R variants. MC4R heterozygous mice show reduced response compared to wild-type mice, while MC4R knockout mice fail to respond entirely, confirming on-target mechanism. Cell-based signaling assays (cAMP, NFAT luciferase), MC4R heterozygous and knockout mouse pharmacology, clinical observation in LEPR-deficient humans Nature medicine Medium 29736023
2017 Setmelanotide is significantly more potent at MC4R than endogenous α-MSH and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants, indicating differential pharmacology at mutant vs wild-type receptors. Cell-based cAMP signaling assays comparing setmelanotide vs α-MSH across 369 annotated MC4R variants, MC4R knockout mouse pharmacology Molecular metabolism Medium 29031731
2010 Multiple obesity-causing MC4R mutations lead to intracellular retention of the receptor. Pharmacological chaperones (cell-permeant MC4R-selective ligands) restore cell surface expression and functional activity of retained mutant MC4Rs with mutation-specific efficacy profiles, demonstrating that misfolding/mistrafficking is the primary defect in these mutants. Cell surface expression assays (flow cytometry/ELISA), cAMP functional assays, 10 different obesity-causing MC4R mutants tested with 5 pharmacological chaperones The Journal of pharmacology and experimental therapeutics Medium 20826565
2003 Over 54% of obesity-associated MC4R mutations impair membrane expression (cell surface trafficking), while the remaining mutations impair basal constitutive activity and/or EC50 for α-MSH as measured by cAMP-dependent luciferase assay. The extent of functional impairment ranges from complete loss to mild reduction in constitutive activity. Flow cytometry-based cell surface expression assay, cAMP-dependent luciferase assay, 50 obesity-associated MC4R mutations characterized, structure modeling Annals of the New York Academy of Sciences Medium 12851297
2015 The synthetic MC4R agonist MTII, unlike α-MSH, induces a persistent cAMP signal that continues for at least 1 hour after agonist removal and cannot be antagonized by AgRP. MTII-exposed MC4R continues to signal after internalization, whereas α-MSH withdrawal causes rapid reversal of cAMP. This demonstrates temporal signaling selectivity linked to different receptor compartments. FRET-based temporal cAMP assay in Neuro2A cells, FRAP assay for receptor internalization, immortalized hypothalamic neurons (mHypoE-42), AMPK signaling measurements Molecular endocrinology Medium 26418335
2014 Mild lipid stress (elevated palmitate at physiological levels) induces mild ER stress and causes profound posttranscriptional loss of MC4R protein abundance in hypothalamic neurons, reducing cAMP signaling in response to α-MSH. Treatment with chemical chaperone 4-phenylbutyrate restores MC4R protein levels and corrects signaling, demonstrating ER-quality-control-mediated regulation of MC4R. Palmitate treatment of mHypoE-42 hypothalamic neurons and Neuro2A cells expressing HA-MC4R-GFP, XBP1 splicing assay for ER stress, cAMP signaling, flow cytometry for protein abundance Molecular endocrinology Medium 24506538
2012 The obesity-linked MC4R P272L mutation is retained in the endoplasmic reticulum not due to misfolding but due to increased propensity to be ubiquitinated in the ER. Inhibition of ubiquitin activating enzyme E1 with UBE-41 rescued cell surface expression and signaling of P272L to wild-type levels, whereas chemical chaperones had minimal effect, distinguishing ubiquitin-mediated ER retention from misfolding-based retention. Immunofluorescence/confocal microscopy for ER localization, cell surface expression assay, cAMP signaling assay, UBE-41 (E1 inhibitor) treatment, PBA chemical chaperone treatment, ubiquitination assays PloS one Medium 23251400
2019 Hypothalamic C2CD5, a C2-domain protein, interacts with MC4R endocytosis machinery and regulates MC4R internalization in hypothalamic neurons. Loss of functional C2CD5 (lacking the C2 domain) blunts MC4R endocytosis and increases MC4R at the cell surface in a state that fails to respond to MC4R ligand. C2CD5 expression is decreased in diet-induced obesity. In situ hybridization, antibody feeding endocytosis assay in Neuro2A cells stably expressing HA-MC4R-GFP, flow cytometry, C2CD5 KO mouse metabolic phenotyping, stereotaxic MTII injection Metabolism: clinical and experimental Medium 31666192
2020 The MC4R F51L mutation produces a specific defect in MC4R/Gq/11α signaling without affecting Gsα/cAMP signaling, and leads to obesity, hyperphagia, and increased linear growth in mice. Delivery of a specific Gq/11α inhibitor to the PVN of wild-type mice abolishes the ability of melanocortin agonists to acutely inhibit food intake, demonstrating that Gq/11α signaling is required for MC4R's acute anorectic effects. Knock-in mouse model (MC4RF51L), signaling assays (cAMP, IP1 for Gq), stereotaxic Gq/11α inhibitor delivery to PVN, food intake measurements, metabolic phenotyping The Journal of clinical investigation High 38175730
2021 MC4R-expressing neurons in the paraventricular nucleus (PVN) project to brain regions controlling feeding, thermoregulation, and cardiovascular function including preoptic area, parabrachial nucleus, nucleus of solitary tract, and thoracic spinal cord. They receive monosynaptic inputs mainly from hypothalamic nuclei and circumventricular organs. Chemogenetic activation of PVN MC4R neurons suppresses feeding and increases heart rate, blood pressure, and brown adipose tissue temperature. Viral circuit mapping (anterograde/retrograde tracing), chemogenetics (DREADD), telemetric cardiovascular monitoring, BAT temperature measurement Molecular metabolism Medium 34823066
2018 Hypothalamic POMC and MC4R (specifically in the PVH) are required for normal counterregulatory responses to hypoglycemia. MC4R-deficient mice show impaired epinephrine and glucagon secretion in response to hypoglycemia, and MC4R agonist (MTII) infused into the PVH restores counterregulatory response in diabetic mice. Region-specific POMC and MC4R knockout mice, hyperinsulinemic-hypoglycemic clamp, stereotaxic MTII infusion, measurement of counterregulatory hormones Molecular metabolism Medium 30503832
2024 Hypothalamic POMC neuron-specific knockout of MC4R in the arcuate nucleus affects energy expenditure and insulin sensitivity by regulating the inwardly rectifying potassium channel Kir2.1. Co-immunoprecipitation demonstrated a direct interaction between MC4R and Kir2.1. Knockdown of Kir2.1 in POMC-MC4R knockout mice restored energy expenditure and ameliorated insulin resistance. POMC-Cre x MC4R-flox conditional knockout, Co-immunoprecipitation (Co-IP) in GT1-7 cells, AAV-shRNA knockdown of Kir2.1 in ARC, metabolic cage measurements, micro-CT body composition Molecular medicine Medium 38448811
2020 Human MRAP2 variants associated with obesity impair multiple MC4R signaling pathways including Gs-cAMP, Gq-IP3, β-arrestin recruitment, and internalization. Structural models predicted that MRAP2 interacts with MC4R transmembrane helices 5 and 6, and mutations in putative contact residues impair MRAP2-facilitated MC4R signaling. MRAP2 variants had no effect on total or cell surface expression of MC4R. cAMP signaling assay, IP3/Gq signaling assay, β-arrestin recruitment assay, internalization assay, cell surface expression assay, structural modeling, 12 MRAP2 variants characterized Human molecular genetics Medium 39807633
2017 Chicken MC4R and MC3R interact with MRAP2 (demonstrated by co-immunoprecipitation), and co-expression with MRAP2 increases their sensitivity to ACTH, making them preferentially ACTH-responsive. AgRP functions as both an inverse agonist (inhibiting constitutive activity) and antagonist (blocking ACTH/α-MSH action) for MC4R. MRAP2 modulates MC4R constitutive activity. Co-immunoprecipitation, CHO cell expression with pGL3-CRE-luciferase reporter assay, dual-luciferase constitutive activity assay The Journal of endocrinology Medium 28512117
2020 MC4R (Asp298Asn substitution in pigs) loses basal constitutive activity and shows decreased cell surface expression compared to wild-type. Both pig MC4R variants interact with pMRAP2 (shown by Co-IP and Nano-HiBiT system), which decreases receptor surface expression and enhances ligand sensitivity to ACTH, though MRAP2 cannot affect the constitutive activity of MC4RAsn (which lacks it). Co-immunoprecipitation, Nano-HiBiT cell surface expression assay, pGL3-CRE-luciferase reporter for cAMP/PKA signaling, dual-luciferase constitutive activity assay Animal genetics Medium 32738077
2021 In pharmacological chaperone (PC) mouse studies, the R165W-hMC4R mutant causes obesity due to misfolding and intracellular retention. Administration of a PC that rescues cell surface expression and functional activity of R165W-hMC4R in cells restored the anorexigenic response to melanocortin agonist in vivo in humanized knock-in mice, providing proof-of-principle for PC therapy. Human WT MC4R shows lower sensitivity to α-MSH (but not β-MSH or MTII) compared to mouse MC4R. Humanized MC4R knock-in mice, in vivo pharmacological chaperone administration, food intake measurement after melanocortin agonist challenge, species comparison of receptor pharmacology JCI insight Medium 33434184
2021 MC4R signaling in the periaqueductal gray (PAG) opposes OPRM1 (mu-opioid receptor) signaling in the regulation of nociception. In red-haired mice (Mc1r loss-of-function), decreased systemic α-MSH levels reduce MC4R activation in the PAG, which derepresses central opioid tone via OPRM1, raising nociceptive thresholds. Mouse genetic models (Mc1r null, MC4R-deficient), melanocyte transplantation, systemic α-MSH measurement, PAG-targeted pharmacology, nociceptive threshold testing Science advances Medium 33811065
2020 MC4R F51L mutation produces a specific defect in Gq/11α signaling. MC4R-null mice can suppress food intake and counteract enforced weight gain after overfeeding, but their rate of weight recovery is impaired, indicating partial MC4R-independent mechanisms exist for overfeeding defense. MC4R KO mice subjected to overfeeding protocol, food intake monitoring, body weight trajectory analysis Nature communications Low 38331907
2020 DNAJC27 (a heat shock protein elevated in obesity) reduces MC4R-mediated cAMP formation when expressed at increased levels in MC4R ACTOne stable cells, suggesting DNAJC27 acts as a negative regulator of MC4R/cAMP signaling. cAMP assay in MC4R-expressing stable cell line with DNAJC27 overexpression Frontiers in endocrinology Low 32733386
2020 MC4R signaling in the arcuate nucleus (ARC) deficiency promotes food intake and impairs energy expenditure. MC4R deficiency in MC4R KO mice was also associated with hypoadiponectinemia and elevated macrophage infiltration of adipose tissue, linking MC4R deficiency to adipose inflammation and insulin resistance. Mc4r knockout mouse model on low-fat and high-fat diet, real-time PCR for macrophage markers, immunohistochemistry, serum adiponectin measurement Obesity (Silver Spring, Md.) Low 18070757
2020 MC4R mutations (specifically in MC4R deficient obese patients) are characterized by hyperphagia and impaired satiety, consistent with MC4R's role in satiety signaling. Loss-of-function mutations in LEPR or MC4R both cause the same phenotype of impaired satiety and hyperphagia. Clinical case series with child eating behavior questionnaire, appetite visual analogue scales, methylphenidate intervention Pediatric obesity Low 31670905

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 363 28273060
2020 Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. The lancet. Diabetes & endocrinology 351 33137293
2018 MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nature medicine 235 29736023
2017 Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Molecular metabolism 226 29031731
2019 Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell 214 31002796
2008 The common obesity variant near MC4R gene is associated with higher intakes of total energy and dietary fat, weight change and diabetes risk in women. Human molecular genetics 166 18697794
2015 G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature 154 25600267
2010 Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. The Journal of neuroscience : the official journal of the Society for Neuroscience 111 20220015
2007 The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. International journal of obesity (2005) 105 17356525
2021 Oestrogen engages brain MC4R signalling to drive physical activity in female mice. Nature 102 34646010
2012 Association between common polymorphism near the MC4R gene and obesity risk: a systematic review and meta-analysis. PloS one 102 23049848
2001 A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. The Journal of clinical endocrinology and metabolism 92 11443223
2003 Molecular genetics of human obesity-associated MC4R mutations. Annals of the New York Academy of Sciences 88 12851297
2011 FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PloS one 86 21283731
2010 Evidences on three relevant obesogenes: MC4R, FTO and PPARγ. Approaches for personalized nutrition. Molecular nutrition & food research 79 21207518
2010 Pharmacological chaperones restore function to MC4R mutants responsible for severe early-onset obesity. The Journal of pharmacology and experimental therapeutics 71 20826565
2018 Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment. The Journal of clinical endocrinology and metabolism 69 29726959
2015 Regulation of glucose tolerance and sympathetic activity by MC4R signaling in the lateral hypothalamus. Diabetes 65 25605803
2020 Association between MC4R rs17782313 genotype and obesity: A meta-analysis. Gene 64 31954858
2012 Statistical and biological gene-lifestyle interactions of MC4R and FTO with diet and physical activity on obesity: new effects on alcohol consumption. PloS one 64 23284998
2021 Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation. Cell reports 62 33761344
2017 The interaction of MC3R and MC4R with MRAP2, ACTH, α-MSH and AgRP in chickens. The Journal of endocrinology 48 28512117
2012 Common polymorphism near the MC4R gene is associated with type 2 diabetes: data from a meta-analysis of 123,373 individuals. Diabetologia 48 22869321
2014 Association between MC4R rs17782313 polymorphism and overeating behaviors. International journal of obesity (2005) 47 24827639
2021 Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations. Molecular metabolism 43 34823066
2018 MC4R Agonists: Structural Overview on Antiobesity Therapeutics. Trends in pharmacological sciences 43 29478721
2016 Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort. International journal of obesity (2005) 39 27654141
2007 Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout mice. Obesity (Silver Spring, Md.) 39 18070757
2012 FTO and MC4R gene variants determine BMI changes in children after intensive lifestyle intervention. Clinical biochemistry 38 23201545
2010 Mutations of MC4R gene and its association with economic traits in Qinchuan cattle. Molecular biology reports 38 19714485
2012 MC4R dimerization in the paraventricular nucleus and GHSR/MC3R heterodimerization in the arcuate nucleus: is there relevance for body weight regulation? Neuroendocrinology 36 22327910
2023 MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R. JCI insight 33 36692018
2020 Differential Signaling Profiles of MC4R Mutations with Three Different Ligands. International journal of molecular sciences 32 32059383
2020 Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants. International journal of obesity (2005) 32 32952152
2019 Celastrol Reduces Obesity in MC4R Deficiency and Stimulates Sympathetic Nerve Activity Affecting Metabolic and Cardiovascular Functions. Diabetes 32 30894367
2014 Association between FTO, MC4R, SLC30A8, and KCNQ1 gene variants and type 2 diabetes in Saudi population. Genetics and molecular research : GMR 32 25501231
2024 Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial. The lancet. Diabetes & endocrinology 30 39549719
2020 Melanocortin 4 receptor (MC4R) gene variants in children and adolescents having familial early-onset obesity: genetic and clinical characteristics. European journal of pediatrics 29 32185475
2020 The interaction between the dietary inflammatory index and MC4R gene variants on cardiovascular risk factors. Clinical nutrition (Edinburgh, Scotland) 29 32586686
2024 A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice. The Journal of clinical investigation 25 38175730
2022 Demethyltransferase FTO alpha-ketoglutarate dependent dioxygenase (FTO) regulates the proliferation, migration, invasion and tumor growth of prostate cancer by modulating the expression of melanocortin 4 receptor (MC4R). Bioengineered 25 34787056
2021 Associations of MC4R, LEP, and LEPR Polymorphisms with Obesity-Related Parameters in Childhood and Adulthood. Genes 25 34205732
2021 Evidence from a meta-analysis for association of MC4R rs17782313 and FTO rs9939609 polymorphisms with susceptibility to obesity in children. Diabetes & metabolic syndrome 25 34364300
2015 Temporal cAMP Signaling Selectivity by Natural and Synthetic MC4R Agonists. Molecular endocrinology (Baltimore, Md.) 25 26418335
2014 Rescue of defective MC4R cell-surface expression and signaling by a novel pharmacoperone Ipsen 17. Journal of molecular endocrinology 25 24780838
2019 Effects of the MC4R, CAPN1, and ADSL genes on body weight and purine content in slow-growing chickens. Poultry science 24 31111951
2017 MeQTL analysis of childhood obesity links epigenetics with a risk SNP rs17782313 near MC4R from meta-analysis. Oncotarget 24 27926527
2011 Identification and analysis of MC4R polymorphisms and their association with economic traits of Korean cattle (Hanwoo). Molecular biology reports 23 21735104
2011 Polymorphisms of INSIG2, MC4R, and LEP are associated with obesity- and metabolic-related traits in schizophrenic patients. Journal of clinical psychopharmacology 23 22020349
2020 Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice. Diabetologia 22 33052459
2015 Interaction between common variants of FTO and MC4R is associated with risk of PCOS. Reproductive biology and endocrinology : RB&E 22 26032905
2023 Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss. Journal of medicinal chemistry 21 36802610
2020 MC4R Variant rs17782313 Associates With Increased Levels of DNAJC27, Ghrelin, and Visfatin and Correlates With Obesity and Hypertension in a Kuwaiti Cohort. Frontiers in endocrinology 21 32733386
2019 NPY and NPY receptors in the central control of feeding and interactions with CART and MC4R in Siberian sturgeon. General and comparative endocrinology 21 31394086
2019 Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance. Metabolism: clinical and experimental 21 31666192
2014 Mild lipid stress induces profound loss of MC4R protein abundance and function. Molecular endocrinology (Baltimore, Md.) 21 24506538
2012 A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct folding. PloS one 21 23251400
2022 Association and interaction of the MC4R rs17782313 polymorphism with plasma ghrelin, GLP-1, cortisol, food intake and eating behaviors in overweight/obese Iranian adults. BMC endocrine disorders 20 36123585
2020 The MC4R SNPs, their haplotypes and gene-environment interactions on the risk of obesity. Molecular medicine (Cambridge, Mass.) 20 32770936
2016 Association of the FTO (rs9939609) and MC4R (rs17782313) gene polymorphisms with maternal body weight during pregnancy. Nutrition (Burbank, Los Angeles County, Calif.) 20 27377581
2022 Interaction of MC4R rs17782313 variants and dietary carbohydrate quantity and quality on basal metabolic rate and general and central obesity in overweight/obese women: a cross-sectional study. BMC endocrine disorders 19 35538513
2021 The Impact of Variants in Four Genes: MC4R, FTO, PPARG and PPARGC1A in Overweight and Obesity in a Large Sample of the Brazilian Population. Biochemical genetics 19 34057646
2020 Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R). Physiological research 19 33094623
2018 Association between the DNA methylations of POMC, MC4R, and HNF4A and metabolic profiles in the blood of children aged 7-9 years. BMC pediatrics 19 29598821
2018 Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice. Molecular metabolism 18 30503832
2015 SNPs detected in the yak MC4R gene and their association with growth traits. Animal : an international journal of animal bioscience 18 25757688
2009 Mutations in the melanocortin 4 receptor (MC4R) gene in obese patients in Norway. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 18 19301229
2021 Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity. JCI insight 17 33434184
2021 Endogenous cannabinoids are required for MC4R-mediated control of energy homeostasis. Proceedings of the National Academy of Sciences of the United States of America 17 34654741
2020 Dietary quality indices modifies the effects of melanocortin-4 receptor (MC4R) rs17782313 polymorphism on cardio-metabolic risk factors and hypothalamic hormones in obese adults. BMC cardiovascular disorders 17 32019489
2020 BRS3 in both MC4R- and SIM1-expressing neurons regulates energy homeostasis in mice. Molecular metabolism 16 32229422
2020 The Asp298Asn polymorphism of melanocortin-4 receptor (MC4R) in pigs: evidence for its potential effects on MC4R constitutive activity and cell surface expression. Animal genetics 16 32738077
2019 Combined effect of FTO and MC4R gene polymorphisms on obesity in children and adolescents in Northwest China: a case-control study. Asia Pacific journal of clinical nutrition 15 30896429
2019 Sex-dependent effects of MC4R genotype on HPA axis tone: implications for stress-associated cardiometabolic disease. Stress (Amsterdam, Netherlands) 15 31184537
2014 Melanocortin-4 receptor (MC4R) polymorphisms are associated with growth and meat quality traits in sheep. Molecular biology reports 15 25048291
2010 Polymorphisms in MC4R gene and correlations with economic traits in cattle. Molecular biology reports 15 20563647
2023 The rs17782313 polymorphism near MC4R gene confers a high risk of obesity and hyperglycemia, while PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder: a systematic review and meta-analysis. Frontiers in endocrinology 14 37621650
2025 Tonic ubiquitination of the central body weight regulator melanocortin receptor 4 (MC4R) promotes its constitutive exit from cilia. PLoS biology 13 39899600
2019 MC4R deficiency in pigs results in hyperphagia and ultimately hepatic steatosis without high-fat diet. Biochemical and biophysical research communications 13 31629472
2019 Methylphenidate in children with monogenic obesity due to LEPR or MC4R deficiency improves feeling of satiety and reduces BMI-SDS-A case series. Pediatric obesity 13 31670905
2016 DNA methylations of MC4R and HNF4α are associated with increased triglyceride levels in cord blood of preterm infants. Medicine 13 27583872
2025 Defining Hyperphagia for Improved Diagnosis and Management of MC4R Pathway-Associated Disease: A Roundtable Summary. Current obesity reports 12 39856371
2024 Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R. Nature communications 12 38331907
2020 Selective Survival of Sim1/MC4R Neurons in Diet-Induced Obesity. iScience 12 32438321
2019 Identification of the MC4R start lost mutation in a morbidly obese Brazilian patient. Diabetes, metabolic syndrome and obesity : targets and therapy 12 30863132
2015 MC4R expression in pedunculopontine nucleus involved in the modulation of midbrain dopamine system. International journal of clinical and experimental pathology 12 25973101
2024 Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1. Molecular medicine (Cambridge, Mass.) 11 38448811
2022 Screening of non-syndromic early-onset child and adolescent obese patients in terms of LEP, LEPR, MC4R and POMC gene variants by next-generation sequencing. Journal of pediatric endocrinology & metabolism : JPEM 11 35801948
2022 Improved Growth and High Inheritance of Melanocortin-4 Receptor (mc4r) Mutation in CRISPR/Cas-9 Gene-Edited Channel Catfish, Ictalurus punctatus. Marine biotechnology (New York, N.Y.) 11 35943638
2016 Effects of MC4R, FTO, and NMB gene variants to obesity, physical activity, and eating behavior phenotypes. IUBMB life 11 27634552
2008 Structural analysis and haplotype diversity in swine LEP and MC4R genes. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 11 18363978
2025 Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways. Human molecular genetics 10 39807633
2024 Investigation of setmelanotide, an MC4R agonist, for obesity in individuals with Smith-Magenis syndrome. Obesity research & clinical practice 10 38987029
2023 MC4R in Central and Peripheral Systems. Advanced biology 10 37043700
2022 MC4R biased signalling and the conformational basis of biological function selections. Journal of cellular and molecular medicine 10 35818295
2021 Sex/Gender Modifies the Association Between the MC4R p.Ile269Asn Mutation and Type 2 Diabetes in the Mexican Population. The Journal of clinical endocrinology and metabolism 10 33045043
2021 Reduced MC4R signaling alters nociceptive thresholds associated with red hair. Science advances 10 33811065
2020 Melanocortin Receptor 4 (MC4R) Signaling System in Nile Tilapia. International journal of molecular sciences 10 32987823
2017 Analysis of SNPs of MC4R, GNB3 and FTO gene polymorphism in obese Saudi subjects. African health sciences 10 29937877
2016 A Common Variant and the Transcript Levels of MC4R Gene Are Associated With Adiposity in Children: The IDEFICS Study. The Journal of clinical endocrinology and metabolism 10 27583473

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