Affinage

MC4R

Melanocortin receptor 4 · UniProt P32245

Length
332 aa
Mass
36.9 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MC4R is a central hypothalamic G protein-coupled receptor that integrates hormonal and neuropeptide signals to regulate energy homeostasis, food intake, glucose metabolism, sympathetic outflow, and sexual behavior. It signals through multiple parallel pathways—Gαs/cAMP, Gq/11α, β-arrestin/MAPK, and direct coupling to inwardly rectifying potassium channels (Kir7.1)—with ligand-biased signaling determining physiological outcome: β-arrestin recruitment efficacy, rather than Gαs-cAMP, explains most of the variance in BMI effects of human MC4R variants, and Gq/11α coupling in the PVN acutely suppresses food intake (PMID:31002796, PMID:38175730, PMID:25600267). MC4R localizes to neuronal primary cilia in an MRAP2-dependent manner and undergoes constitutive ciliary exit regulated by β-arrestin, ubiquitination, and the BBSome, while constitutive clathrin- and cholesterol-dependent endocytosis from the plasma membrane recycles phosphorylated receptors through endosomes to maintain agonist responsiveness (PMID:36692018, PMID:39899600, PMID:22544740). Loss-of-function mutations in MC4R—most commonly impairing plasma membrane trafficking due to ER retention or misfolding, and correctable by pharmacological chaperones—constitute the most common monogenic cause of human obesity (PMID:12851297, PMID:20826565, PMID:33761344).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2010 High

    Systematic characterization of 50 obesity-associated MC4R mutations established that haploinsufficiency—driven predominantly by impaired membrane trafficking (>54%) and secondarily by reduced constitutive activity or agonist potency—is the molecular mechanism underlying MC4R-linked obesity.

    Evidence Flow cytometry surface expression and cAMP-luciferase assays across 50 human MC4R variants

    PMID:12851297

    Open questions at the time
    • Signaling pathways beyond Gαs/cAMP not assessed
    • Variant effects on β-arrestin recruitment and biased signaling unknown
    • In vivo trafficking of these variants not confirmed
  2. 2010 High

    Pharmacological chaperones demonstrated that ER retention due to misfolding is the primary loss-of-function mechanism for many obesity-causing MC4R mutations, and that surface expression and signaling can be rescued by cell-permeant ligands.

    Evidence Cell surface expression rescue and cAMP functional assays with pharmacological chaperone treatment of 10 MC4R mutants

    PMID:20826565

    Open questions at the time
    • In vivo pharmacological chaperone efficacy not shown at this stage
    • Potential off-target effects of chaperone ligands on WT MC4R signaling not fully addressed
  3. 2011 High

    The agouti/attractin/MGRN1 axis was shown to regulate MC4R post-endocytic fate: ASP directs MC4R to lysosomes for degradation, while attractin and MGRN1 are required for this sorting, revealing a cAMP-independent trafficking control mechanism for MC4R signaling output.

    Evidence Genetic epistasis in agouti yellow mice combined with receptor trafficking and endosomal/lysosomal fractionation assays

    PMID:21460229

    Open questions at the time
    • Direct ubiquitin ligase activity of MGRN1 on MC4R not demonstrated
    • Whether this pathway operates in human hypothalamic neurons unknown
  4. 2012 High

    Constitutive clathrin- and cholesterol-dependent endocytosis was identified as essential for maintaining MC4R agonist responsiveness, with phosphorylation at Thr-312 and Ser-329 governing endosomal recycling that restores receptor function.

    Evidence Clathrin and cholesterol depletion, phospho-site mutagenesis, cAMP assays in Neuro2A and GT1-7 cells

    PMID:22544740

    Open questions at the time
    • In vivo relevance of constitutive endocytosis to energy homeostasis not tested
    • Identity of kinase(s) phosphorylating T312/S329 not established
  5. 2012 High

    Ubiquitin-dependent ER quality control was established as a mechanism causing intracellular retention of correctly folded MC4R variants (P272L), and pharmacological E1 inhibition rescued surface expression, distinguishing misfolding from ubiquitination as independent retention mechanisms.

    Evidence Ubiquitination assays, ER localization, E1 inhibitor rescue, cAMP assays in neuronal cells

    PMID:23251400

    Open questions at the time
    • Specific E3 ligase responsible for MC4R ubiquitination at the ER not identified
    • Generalizability to other MC4R variants not systematically tested
  6. 2015 High

    MC4R was shown to couple directly to Kir7.1 in PVN neurons independently of Gαs, and AgRP was redefined as a biased agonist that opens Kir7.1 to hyperpolarize neurons rather than simply an inverse agonist—establishing a Gαs-independent effector pathway for MC4R.

    Evidence Electrophysiology in PVN neurons with pharmacological ligand dissection

    PMID:25600267

    Open questions at the time
    • Molecular mechanism linking MC4R to Kir7.1 (adaptor proteins, direct binding) not resolved
    • Contribution of Kir7.1 pathway to long-term energy balance not tested
  7. 2015 High

    Site-specific MC4R restoration in the lateral hypothalamic area demonstrated that MC4R controls glucose tolerance and sympathetic outflow to brown adipose tissue independently of body weight, establishing an anatomically discrete metabolic role.

    Evidence LHA-specific MC4R re-expression in MC4R-null mice, direct sympathetic nerve recording, BAT denervation epistasis

    PMID:25605803

    Open questions at the time
    • Downstream signaling pathway in LHA neurons not identified
    • Relevance to human glucose regulation not confirmed
  8. 2015 High

    Temporal signaling selectivity was demonstrated for MC4R: the synthetic agonist MTII produces persistent, internalization-resistant cAMP signaling whereas α-MSH signaling is rapidly reversible and antagonizable by AgRP, revealing agonist-dependent control of signaling duration.

    Evidence Real-time FRET-based cAMP imaging, FRAP for internalized receptor signaling in Neuro2A and mHypoE-42 cells

    PMID:26418335

    Open questions at the time
    • Structural basis of prolonged MTII-MC4R signaling not determined
    • In vivo consequences of sustained versus pulsatile cAMP signaling not tested
  9. 2018 High

    Palmitoylation at Cys318/Cys319 in the MC4R C-terminus was shown to be essential for receptor surface expression and signaling, and setmelanotide was found to uniquely activate NFAT signaling in addition to canonical cAMP, demonstrating that therapeutic MC4R agonists can engage distinct downstream pathways.

    Evidence C-terminal truncation mutagenesis with lipid modification assays; NFAT reporter and cAMP assays with setmelanotide

    PMID:29736023 PMID:29991773

    Open questions at the time
    • Whether NFAT pathway activation is required for weight loss in patients not established
    • Enzymatic machinery for MC4R palmitoylation not identified
  10. 2018 High

    MC4R in Sim1-positive neurons (PVN and medial amygdala) was shown to be sufficient for male sexual function, and MC4R in the PVH was required for counterregulatory responses to hypoglycemia, broadening the receptor's functional repertoire beyond satiety.

    Evidence Cre-dependent MC4R re-expression in Sim1 neurons with behavioral scoring; PVH-targeted MC4R agonist infusion during hypoglycemic clamps

    PMID:29059347 PMID:30503832

    Open questions at the time
    • Downstream signaling pathways mediating sexual behavior not identified
    • Whether human MC4R mutations affect sexual or counterregulatory function not tested
  11. 2019 High

    Analysis of 61 MC4R variants from the UK Biobank revealed that β-arrestin recruitment efficacy—not Gαs/cAMP signaling—explains 88% of variance in BMI association, and gain-of-function variants biased toward β-arrestin/MAPK are protective against obesity, fundamentally redefining the therapeutically relevant signaling pathway.

    Evidence Parallel cAMP, β-arrestin, and MAPK assays for 61 variants correlated with UK Biobank BMI data

    PMID:31002796

    Open questions at the time
    • Downstream effectors of β-arrestin-biased MC4R signaling in hypothalamic neurons not mapped
    • Whether β-arrestin-biased MC4R agonists would be superior therapeutics not tested in vivo
  12. 2021 High

    Comprehensive trafficking analysis of human MC4R variants showed that obesity-associated mutations predominantly impair surface trafficking while protective mutations enhance recycling or reduce internalization; MC4R was demonstrated to form homodimers, and disruption of dimerization is pathogenic even without loss of Gαs signaling.

    Evidence Surface expression, internalization, β-arrestin recruitment, and dimerization assays across human variant panel

    PMID:33761344

    Open questions at the time
    • Structural basis of MC4R homodimerization not resolved
    • Functional consequence of dimerization versus monomer signaling at Kir7.1 or Gq not tested
  13. 2021 High

    Pharmacological chaperone rescue was validated in vivo using humanized MC4R knock-in mice carrying the R165W mutation, demonstrating that PC treatment restores anorexigenic agonist responsiveness and confirming the translational potential of the chaperone approach.

    Evidence Humanized R165W-hMC4R knock-in mice, in vivo PC administration, body weight, food intake, and ex vivo signaling

    PMID:33434184

    Open questions at the time
    • Long-term efficacy and safety of pharmacological chaperones not assessed
    • Species differences in MC4R α-MSH sensitivity may affect clinical translation
  14. 2021 High

    Endocannabinoid 2-AG synthesis within MC4R-expressing PVN neurons was shown to regulate afferent GABAergic tone onto these neurons; loss of 2-AG synthesis caused hypophagia, increased energy expenditure, and MC4R agonist insensitivity, revealing a local modulatory circuit.

    Evidence Conditional knockout of 2-AG synthesis in MC4R neurons, electrophysiology, chemogenetics, metabolic phenotyping

    PMID:34654741

    Open questions at the time
    • Whether 2-AG acts on MC4R directly or exclusively through CB1 on presynaptic terminals not definitively resolved
    • Relevance of this mechanism to human obesity pharmacology unknown
  15. 2023 High

    MRAP2 was identified as essential for targeting MC4R to neuronal primary cilia, and ciliary MC4R localization was shown to be required for long-term energy homeostasis, linking MC4R to the ciliopathy-obesity connection.

    Evidence In vivo viral manipulation, ciliary localization imaging, MC4R-MRAP2 interaction studies, energy balance phenotyping in mice

    PMID:36692018

    Open questions at the time
    • Mechanism by which MRAP2 promotes ciliary targeting not molecularly defined
    • Whether ciliary versus plasma membrane MC4R engages different signaling pathways not established
  16. 2024 High

    Gq/11α signaling through MC4R in the PVN was identified as a major contributor to acute food intake suppression and linear growth regulation, using a knock-in mutation (F51L) that selectively disrupts Gq coupling, resolving longstanding uncertainty about which G protein mediates the anorexigenic signal.

    Evidence MC4R-F51L knock-in mice, PVN-targeted Gq/11α inhibitor injection, in vitro multi-pathway signaling assays

    PMID:38175730

    Open questions at the time
    • Relative contributions of Gq, β-arrestin, and Kir7.1 pathways to chronic body weight regulation not resolved
    • Whether Gq signaling at the cilium differs from that at the plasma membrane not tested
  17. 2025 High

    The dynamic ciliary trafficking cycle of MC4R was mapped: constitutive receptor activity drives ciliary exit via β-arrestin, ubiquitination, and the BBSome, while AgRP suppresses constitutive activity to accumulate MC4R in cilia, integrating ciliary biology with ligand pharmacology.

    Evidence Live imaging of ciliary MC4R dynamics, pharmacological and genetic manipulation of β-arrestin, BBSome, and ubiquitination pathways

    PMID:39899600

    Open questions at the time
    • Identity of the E3 ubiquitin ligase responsible for ciliary MC4R ubiquitination not determined
    • Whether ciliary accumulation of MC4R by AgRP is pro- or anti-orexigenic in vivo not clarified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis and stoichiometry of MC4R homodimerization, the identity of E3 ligases controlling MC4R ubiquitination at the ER and cilium, how ciliary versus plasma membrane MC4R pools contribute differentially to signaling, and whether β-arrestin-biased MC4R agonists provide superior therapeutic efficacy for obesity.
  • No structural model of MC4R dimer or MC4R-Kir7.1 complex
  • E3 ligase identity unknown
  • Ciliary vs. plasma membrane signaling partition not resolved
  • β-arrestin-biased agonist efficacy not tested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005929 cilium 2
Pathway
R-HSA-9609507 Protein localization 6 R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 4 R-HSA-1430728 Metabolism 2
Partners
AGRPARRB2C2CD5KCNJ13KCNJ2LCN2MRAP2

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 MC4R couples to the inwardly rectifying potassium channel Kir7.1 in paraventricular nucleus neurons independently of Gαs signaling. α-MSH acting on MC4R closes Kir7.1, while AgRP acts as a biased agonist that opens Kir7.1 via MC4R independently of blocking α-MSH binding, thereby hyperpolarizing neurons. Electrophysiology in PVN neurons, Gαs-independent signaling assays, ligand pharmacology in mice 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. Gain-of-function MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased MAPK pathway activation are protective against obesity. Functional characterization of 61 MC4R variants from UK Biobank; β-arrestin recruitment assays, cAMP assays, MAPK pathway activation assays Cell High 31002796
2017 Lipocalin 2 (LCN2), a bone-derived hormone, crosses the blood-brain barrier and binds to MC4R in paraventricular and ventromedial hypothalamic neurons to activate an MC4R-dependent anorexigenic pathway suppressing appetite. Molecular and genetic analyses in mice; loss- and gain-of-function experiments; binding assays showing LCN2-MC4R interaction Nature High 28273060
2021 Estrogen surges increase MC4R signaling in VMHvl neurons by directly recruiting estrogen receptor-α (ERα) to the Mc4r gene, and MC4R signaling in VMHvl neurons expressing both MC4R and ERα drives physical activity in female mice. Chemogenetic stimulation, CRISPR-mediated activation, ERα ChIP at Mc4r locus, neuron-specific circuit tracing Nature High 34646010
2023 MRAP2 is required for the localization of MC4R to neuronal primary cilia, and ciliary targeting of MC4R is essential for long-term energy homeostasis regulation. In vivo viral manipulation, ciliary localization imaging, MC4R/MRAP2 interaction studies, energy balance phenotyping in mice JCI insight High 36692018
2025 MC4R undergoes constitutive exit from neuronal primary cilia driven by its constitutive activity; AgRP binding to MC4R suppresses this constitutive activity and causes MC4R accumulation in cilia. Ciliary exit requires β-arrestin, ubiquitination, and the BBSome complex, while ciliary targeting requires MRAP2. Live imaging of ciliary MC4R dynamics, pharmacological and genetic manipulation of MC4R activity, β-arrestin and BBSome loss-of-function, ubiquitination assays PLoS biology High 39899600
2012 Constitutive endocytosis of MC4R is clathrin- and cholesterol-dependent, and this constitutive internalization is required to maintain MC4R responsiveness to α-MSH by cycling receptors modified at Thr-312 and Ser-329 through the endosomal compartment to regain function. Clathrin depletion, cholesterol depletion, phosphorylation site mutagenesis (T312A, S329A), cAMP assays in Neuro2A and GT1-7 cells The Journal of biological chemistry High 22544740
2018 Setmelanotide uniquely activates NFAT signaling downstream of MC4R (in addition to canonical cAMP signaling) and can restore function of selected MC4R variants, unlike previously developed MC4R agonists. Cell-based signaling assays (cAMP, NFAT reporter), functional characterization of MC4R variants, clinical observation in LEPR-deficient patients Nature medicine High 29736023
2024 MC4R/Gq/11α signaling (not Gsα) in the paraventricular nucleus significantly contributes to the acute inhibition of food intake and regulation of linear growth; an MC4RF51L mutation specifically disrupts Gq/11α coupling leading to hyperphagia and obesity in mice. Knock-in mouse model (MC4RF51L), Gq/11α-specific inhibitor delivered to PVN, in vitro signaling assays, food intake measurements The Journal of clinical investigation High 38175730
2021 Most obesity-associated MC4R mutations impair trafficking to the plasma membrane; obesity-protecting mutations either accelerate recycling to the plasma membrane or decrease internalization. MC4R forms homodimers, and multiple obesity-associated mutations disrupt homodimerization. Mutations that do not affect Gαs signaling but disrupt agonist-induced internalization, β-arrestin recruitment, or homodimerization are nonetheless pathogenic. Cell surface expression assays, internalization assays, β-arrestin recruitment assays, structural mapping, dimerization studies using human MC4R mutations Cell reports High 33761344
2015 MC4R signaling in the lateral hypothalamic area (LHA) regulates glucose tolerance and sympathetic nerve activity to brown adipose tissue independently of body weight. Restoring MC4R specifically in the LHA increases sympathetic traffic to interscapular BAT, elevates Glut4 expression in BAT, and improves glucose tolerance, an effect abolished by bilateral BAT denervation. Site-specific MC4R restoration in MC4R-null mice, fluorodeoxyglucose tracing, direct multifiber sympathetic nerve recording, bilateral BAT denervation Diabetes High 25605803
2016 A functional POMC circuit in the mouse hippocampus exists wherein POMC neurons in CA3 activate MC4R in CA1. MC4R activation rescues amyloid-β-induced synaptic dysfunction via a Gs/cAMP/PKA/CREB-dependent mechanism. Circuit mapping, LTP recordings, pharmacological MC4R activation/inhibition, PKA/CREB signaling assays in APP/PS1 transgenic mice Cell reports High 27829153
2011 Agouti-signaling protein (ASP) inhibits MC4R by blocking ligand binding and directing MC4R trafficking to the lysosome for degradation. Loss of attractin (mahogany) or MGRN1 (mahoganoid) blocks ASP-dependent MC4R lysosomal degradation and promotes MC4R trafficking to the cell surface, rescuing the Agouti yellow mouse phenotype via a cAMP-independent mechanism. cAMP assays, receptor trafficking assays, endosomal/lysosomal fractionation, genetic epistasis in mice The Journal of biological chemistry High 21460229
2010 Over 54% of obesity-associated MC4R mutations impair membrane expression (assessed by flow cytometry-based assay); all remaining mutations impair basal constitutive activity and/or EC50 for α-MSH as measured by cAMP-dependent luciferase assay, indicating haploinsufficiency as the mechanism of obesity. Flow cytometry cell surface expression assay, cAMP-dependent luciferase assay, functional characterization of 50 MC4R mutations Annals of the New York Academy of Sciences High 12851297
2010 Pharmacological chaperones (cell-permeant MC4R-selective ligands) restore cell surface expression and function of mutant MC4R variants responsible for obesity, demonstrating that intracellular retention by misfolding is the mechanism of loss of function for many obesity-causing mutations. Cell surface expression assays, pharmacological chaperone treatment, functional cAMP assays for 10 MC4R mutants The Journal of pharmacology and experimental therapeutics High 20826565
2021 Endogenous cannabinoid 2-arachidonoylglycerol (2-AG) regulates the activity of MC4R neurons in the PVN via inhibition of afferent GABAergic drive; impaired 2-AG synthesis within MC4R neurons leads to hypophagia, increased energy expenditure, and resistance to diet-induced obesity, and also causes MC4R agonist insensitivity. Conditional knockout of 2-AG synthesis in MC4R neurons, electrophysiology, chemogenetics, energy balance phenotyping Proceedings of the National Academy of Sciences of the United States of America High 34654741
2021 PVN MC4R neurons (PVNMC4R+) receive monosynaptic inputs primarily from hypothalamic nuclei and project broadly to brain regions controlling neuroendocrine and autonomic functions. Chemogenetic activation of PVNMC4R+ neurons suppresses feeding, increases heart rate, blood pressure, and brown adipose tissue temperature. Viral circuit mapping (monosynaptic tracing), chemogenetic activation (DREADD), physiological monitoring of heart rate, blood pressure, BAT temperature Molecular metabolism High 34823066
2018 MC4R is lipid-modified at cysteine318 and cysteine319 in the C-terminus; truncation before cysteine318 eliminates receptor surface expression and signaling (loss of function), while truncation after this site is tolerated, establishing this region as critical for MC4R trafficking and function. C-terminal truncation mutagenesis, lipid modification assays, cell surface expression assays, patient variant analysis Scientific reports High 29991773
2012 MC4R P272L mutation is retained in the endoplasmic reticulum due to increased ubiquitination despite correct protein folding; inhibition of ubiquitin-activating enzyme E1 (with UBE-41) restores cell surface expression and signaling of P272L to near wild-type levels. ER localization assays, ubiquitination assays, E1 inhibitor treatment, cell surface ELISA, cAMP assays in neuronal cells PloS one High 23251400
2015 The synthetic MC4R agonist melanotan II (MTII) induces a prolonged cAMP signal that persists after agonist removal and cannot be antagonized by AgRP, in contrast to α-MSH which produces rapidly reversible cAMP signaling. MTII continues to signal after receptor internalization, demonstrating temporal cAMP signaling selectivity dependent on the agonist used. FRET-based temporally resolved cAMP assay, FRAP assay, internalization assays in Neuro2A and mHypoE-42 cells Molecular endocrinology High 26418335
2014 Mild lipid stress (elevated palmitate) causes profound loss of MC4R protein abundance via posttranscriptional mechanisms (ER stress), leading to reduced cAMP signaling in response to α-MSH in hypothalamic neurons; this is corrected by chemical chaperone 4-phenylbutyrate. Palmitate treatment of hypothalamic neurons (mHypoE-42) and Neuro2A cells, XBP1 splicing assay, cAMP assay, protein quantification, chemical chaperone rescue Molecular endocrinology High 24506538
2018 Hypothalamic C2CD5 interacts with endocytosis machinery and regulates MC4R endocytosis. Loss of functional C2CD5 blunts MC4R endocytosis, increases MC4R at the surface that fails to respond to MC4R ligand, and blunts acute feeding responses to MC4R agonist MTII injected into the PVH. In vivo KO mouse phenotyping, antibody feeding endocytosis assay in Neuro2A cells, interaction assays with endocytic machinery, MTII injection into PVH Metabolism: clinical and experimental Medium 31666192
2018 Sim1-positive neurons are sufficient for MC4R-mediated male sexual function; selective re-expression of MC4R on Sim1 neurons (including medial amygdala and PVN) reverses the sexual behavior deficits seen in MC4R-null mice. Cre-dependent MC4R re-expression in Sim1 neurons, sexual behavior scoring (mounting, intromission, ejaculation) in tbMC4R null mice Endocrinology High 29059347
2018 MC4R deficiency in mice is associated with impaired counterregulatory responses to hypoglycemia (reduced epinephrine and glucagon release); MC4R agonist infusion into the PVH restores the counterregulatory response in diabetic mice. POMC- and MC4R-deficient mouse models, hyperinsulinemic-hypoglycemic clamp, stereotaxic MC4R agonist injection into PVH, hormone measurements Molecular metabolism High 30503832
2019 MC4R mediates JNK signaling pathway activation in the context of neuropathic pain; MC4R inhibition with HS014 reduces p-JNK, ATF3, and c-Jun levels and alleviates nociceptive behavior after chronic constriction injury. Rat CCI model, MC4R inhibitor treatment, qRT-PCR, Western blot, immunohistochemistry, immunofluorescence, MC4R overexpression in astrocytes Frontiers in neuroscience Medium 31551683
2024 MC4R directly interacts with Kir2.1 (demonstrated by Co-IP) in the arcuate nucleus, and POMC neuron-specific knockout of MC4R promotes food intake and impairs energy expenditure; knockdown of Kir2.1 in these neurons restores normal energy balance and insulin sensitivity. POMC-specific MC4R conditional knockout, Co-immunoprecipitation of MC4R and Kir2.1 in GT1-7 cells, AAV-mediated Kir2.1 knockdown, metabolic phenotyping Molecular medicine Medium 38448811
2019 Sex-dependent effects of MC4R on HPA axis tone: MC4R loss-of-function blunts basal HPA axis tone and acute stress responsivity in males but exaggerates these responses in females. MC4R loss-of-function rats, chronic variable stress, acute restraint stress challenge, adrenal weight measurement, corticosterone measurement Stress Medium 31184537
2020 MC4R S127L mutation leads to full loss of function across all signaling pathways tested (Gs, Gi, Gq/11, G12/13, ERK phosphorylation, β-arrestin2); V103I and H158R mutations show signaling bias toward the Gq/11 pathway when stimulated with endogenous ligands α-MSH and β-MSH. Comprehensive G protein family signaling assays, ERK phosphorylation, β-arrestin2 recruitment assays with multiple agonists International journal of molecular sciences High 32059383
2011 Aminoglycoside-mediated read-through of MC4R nonsense mutations (W16X, Y35X, E61X, Q307X) restores full-length receptor protein; functional rescue depends on the triplet sequence of the stop codon, surrounding sequence, and location within the receptor, with N-terminal stop mutations being more rescuable than those in transmembrane domains. Fluorescence microscopy, cell surface and total ELISA, cAMP assays, aminoglycoside treatment of COS-7 cells expressing MC4R stop mutants Obesity Medium 21738238
2021 In pharmacological chaperone (PC) humanized MC4R mouse models, administration of a PC restores cell surface expression and functional activity of the R165W-hMC4R mutant, rescuing the anorexigenic response to melanocortin agonist in vivo. Human MC4R shows lower sensitivity to α-MSH but not β-MSH or melanotan II compared to mouse MC4R. Humanized knock-in mouse models, PC administration in vivo, body weight and food intake measurements, ex vivo receptor signaling assays JCI insight High 33434184
2010 Conditional postnatal deletion of Sim1 causes hyperphagic obesity accompanied by decreased hypothalamic oxytocin and PVN MC4R mRNA expression, without global PVN hypocellularity or disrupted PVN projections, placing Sim1 upstream of the MC4R/oxytocin pathway in feeding regulation. CaMKII-Cre conditional Sim1 deletion, stereological cell counting, retrograde tract tracing, in situ hybridization for Mc4r and Oxt mRNA The Journal of neuroscience High 20220015

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 354 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 336 33137293
2018 MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nature medicine 228 29736023
2017 Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Molecular metabolism 220 29031731
2019 Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity. Cell 211 31002796
2015 G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature 154 25600267
2015 RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. The Journal of clinical endocrinology and metabolism 126 25675384
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
2021 Oestrogen engages brain MC4R signalling to drive physical activity in female mice. Nature 96 34646010
1997 Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. Journal of medicinal chemistry 91 9216831
2003 Molecular genetics of human obesity-associated MC4R mutations. Annals of the New York Academy of Sciences 87 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 65 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
2021 Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation. Cell reports 59 33761344
2011 The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women. PloS one 58 21347432
2003 The human MC4R promoter: characterization and role in obesity. Diabetes 56 14633862
2007 Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE. Human mutation 50 17072869
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
2016 Stimulation of the Hippocampal POMC/MC4R Circuit Alleviates Synaptic Plasticity Impairment in an Alzheimer's Disease Model. Cell reports 47 27829153
2014 Association between MC4R rs17782313 polymorphism and overeating behaviors. International journal of obesity (2005) 47 24827639
2018 Association between LEPR, FTO, MC4R, and PPARG-2 polymorphisms with obesity traits and metabolic phenotypes in school-aged children. Endocrine 45 29679223
2021 Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations. Molecular metabolism 43 34823066
2011 Rescue of melanocortin 4 receptor (MC4R) nonsense mutations by aminoglycoside-mediated read-through. Obesity (Silver Spring, Md.) 40 21738238
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
2014 A novel MC4R mutation associated with childhood-onset obesity: A case report. Paediatrics & child health 36 25587224
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
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
2020 Differential Signaling Profiles of MC4R Mutations with Three Different Ligands. International journal of molecular sciences 31 32059383
2023 MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R. JCI insight 30 36692018
2020 The interaction between the dietary inflammatory index and MC4R gene variants on cardiovascular risk factors. Clinical nutrition (Edinburgh, Scotland) 29 32586686
2012 Constitutive cholesterol-dependent endocytosis of melanocortin-4 receptor (MC4R) is essential to maintain receptor responsiveness to α-melanocyte-stimulating hormone (α-MSH). The Journal of biological chemistry 28 22544740
2011 Mahoganoid and mahogany mutations rectify the obesity of the yellow mouse by effects on endosomal traffic of MC4R protein. The Journal of biological chemistry 28 21460229
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
2021 Associations of MC4R, LEP, and LEPR Polymorphisms with Obesity-Related Parameters in Childhood and Adulthood. Genes 24 34205732
2015 Temporal cAMP Signaling Selectivity by Natural and Synthetic MC4R Agonists. Molecular endocrinology (Baltimore, Md.) 24 26418335
2019 Analysis of the Role of the Mc4r System in Development, Growth, and Puberty of Medaka. Frontiers in endocrinology 23 31024451
2019 Effects of the MC4R, CAPN1, and ADSL genes on body weight and purine content in slow-growing chickens. Poultry science 23 31111951
2017 MeQTL analysis of childhood obesity links epigenetics with a risk SNP rs17782313 near MC4R from meta-analysis. Oncotarget 23 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
2024 A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice. The Journal of clinical investigation 22 38175730
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 22 39549719
2019 Characterization of Rare Variants in MC4R in African American and Latino Children With Severe Early-Onset Obesity. The Journal of clinical endocrinology and metabolism 22 30811542
2018 Insights into the Allosteric Mechanism of Setmelanotide (RM-493) as a Potent and First-in-Class Melanocortin-4 Receptor (MC4R) Agonist To Treat Rare Genetic Disorders of Obesity through an in Silico Approach. ACS chemical neuroscience 22 30048591
2016 Prevalence of mutations in LEP, LEPR, and MC4R genes in individuals with severe obesity. Genetics and molecular research : GMR 22 27706562
2015 Interaction between common variants of FTO and MC4R is associated with risk of PCOS. Reproductive biology and endocrinology : RB&E 22 26032905
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
2019 Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance. Metabolism: clinical and experimental 20 31666192
2018 Heterozygous versus homozygous phenotype caused by the same MC4R mutation: novel mutation affecting a large consanguineous kindred. BMC medical genetics 20 30068297
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 19 36123585
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 The MC4R SNPs, their haplotypes and gene-environment interactions on the risk of obesity. Molecular medicine (Cambridge, Mass.) 19 32770936
2016 Association of the FTO (rs9939609) and MC4R (rs17782313) gene polymorphisms with maternal body weight during pregnancy. Nutrition (Burbank, Los Angeles County, Calif.) 19 27377581
2023 Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss. Journal of medicinal chemistry 18 36802610
2020 Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R). Physiological research 18 33094623
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
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
2021 Pharmacological chaperone action in humanized mouse models of MC4R-linked obesity. JCI insight 16 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 16 34654741
2018 Sim1 Neurons Are Sufficient for MC4R-Mediated Sexual Function in Male Mice. Endocrinology 16 29059347
2015 Associations between a common variant near the MC4R gene and serum triglyceride levels in an obese pediatric cohort. Endocrine 16 25948074
2020 BRS3 in both MC4R- and SIM1-expressing neurons regulates energy homeostasis in mice. Molecular metabolism 15 32229422
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
2019 MC4R Is Involved in Neuropathic Pain by Regulating JNK Signaling Pathway After Chronic Constriction Injury. Frontiers in neuroscience 14 31551683
2014 Novel variants in the MC4R and LEPR genes among severely obese children from the Iberian population. Annals of human genetics 14 24611737
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
2014 The role of common and rare MC4R variants and FTO polymorphisms in extreme form of obesity. Molecular biology reports 13 24385306
2020 Selective Survival of Sim1/MC4R Neurons in Diet-Induced Obesity. iScience 12 32438321
2017 Rs12970134 near MC4R is associated with appetite and beverage intake in overweight and obese children: A family-based association study in Chinese population. PloS one 12 28520814
2014 Variation in the MC4R gene is associated with bone phenotypes in elderly Swedish women. PloS one 12 24516669
2025 Tonic ubiquitination of the central body weight regulator melanocortin receptor 4 (MC4R) promotes its constitutive exit from cilia. PLoS biology 11 39899600
2024 Protection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R. Nature communications 11 38331907
2024 Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1. Molecular medicine (Cambridge, Mass.) 11 38448811
2023 Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment. Science translational medicine 11 37467315
2019 Identification of the MC4R start lost mutation in a morbidly obese Brazilian patient. Diabetes, metabolic syndrome and obesity : targets and therapy 11 30863132
2018 Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability. Scientific reports 11 29991773
2017 [Generation and phenotype analysis of zebrafish mutations of obesity-related genes lepr and mc4r]. Sheng li xue bao : [Acta physiologica Sinica] 11 28217809
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 Defining Hyperphagia for Improved Diagnosis and Management of MC4R Pathway-Associated Disease: A Roundtable Summary. Current obesity reports 10 39856371
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
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