Affinage

POMC

Pro-opiomelanocortin · UniProt P01189

Length
267 aa
Mass
29.4 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 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

POMC encodes a polyprotein precursor whose protein-coding sequence resides largely within a single large exon downstream of a small signal-peptide exon, with the segment encoding its bioactive peptides (ACTH, β-endorphin, MSH peptides) highly conserved across mammals (PMID:6253815, PMID:6255341). The precursor is cleaved cell-specifically by the prohormone convertases PC1 and PC2, which are co-expressed with POMC peptides and drive differential tissue-specific processing into α-MSH, ACTH, β-MSH, and β-endorphin (PMID:10858267); failure of normal processing yields predominantly ACTH precursors, as seen in ectopic ACTH syndrome (PMID:8137518). The HFRW motif of the processed melanocortin peptides is essential for receptor function: the R8 residue is required for ACTH binding and cAMP activation at MC2R and for α-MSH activation of MC1R and MC4R, and its mutation produces bioinactive hormones (PMID:23293326). Newly synthesized POMC is subject to Sel1L-Hrd1 ERAD quality control that degrades a fraction of nascent protein to prevent misfolded/aggregated accumulation and permit normal processing and secretion (PMID:29457782). In the hypothalamic arcuate nucleus, POMC neurons constitute the anorexigenic arm of the melanocortin system: they are depolarized by leptin and exert autoinhibition through melanocortin peptides (PMID:11373681), comprise functionally distinct Lepr- and Glp1r-defined subpopulations (PMID:34002087), and signal onward through MC4R-expressing target circuits such as the ARC→medial amygdala projection to suppress feeding (PMID:33250721). POMC neuronal activity and Pomc expression integrate hormonal and metabolic inputs — leptin via JAK/STAT and TrpC5 channels (PMID:27500489, PMID:28099839), insulin via PDK-1/FoxO1 and TCPTP (PMID:20103739, PMID:30230471), lactate via astrocytic HCAR1 and direct uptake (PMID:34737351), CB1R, which selectively releases β-endorphin to drive feeding (PMID:25707796), and mitochondrial dynamics governing leptin sensitivity and excitability (PMID:28190775, PMID:28489068). Pomc transcription is repressed by glucocorticoids through a proximal nGRE that competes with COUP factors (PMID:2698828) and via NeuroD1 and SGK1/FOXO3 (PMID:28406939, PMID:29321171), and activated by an RXR-α/LXR-α heterodimer (PMID:19036902), by MeCP2/HDAC2/DNMT1-dependent methylation (PMID:24506071), and by histone lactylation controlled through Fam172a, which also tunes PAM-dependent α-MSH amidation (PMID:39578459). Loss-of-function in POMC peptide signaling underlies human disease, including the bioinactive ACTH/α-MSH phenotype caused by the p.R8C mutation (PMID:23293326).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1980 High

    Established the genomic architecture of the POMC precursor gene, showing that all bioactive peptides are encoded together within a single large, evolutionarily conserved exon.

    Evidence Genomic DNA cloning and sequencing of bovine and rat POMC loci

    PMID:6253815 PMID:6255341

    Open questions at the time
    • Does not address how the single transcript is processed into distinct peptides
    • No tissue-specific regulation defined
  2. 1984 Medium

    Defined glucocorticoid negative feedback on the corticotrope, distinguishing rapid non-genomic suppression of ACTH secretion from slow genomic reduction of POMC mRNA.

    Evidence In vitro corticotrope secretion assays, in vivo pharmacology, POMC mRNA analysis (review of primary data)

    PMID:6323158

    Open questions at the time
    • Molecular DNA elements mediating genomic repression not yet identified
    • Identity of intermediate corticosteroid-dependent protein unknown
  3. 1989 High

    Identified the cis-regulatory basis of glucocorticoid repression, mapping a proximal nGRE that binds glucocorticoid receptor and COUP factors mutually exclusively within a fragment sufficient for pituitary-specific expression.

    Evidence Transgenic mice plus cell culture transfection and DNA-protein binding assays

    PMID:2698828

    Open questions at the time
    • Does not establish in vivo contribution of COUP competition
    • Other regulatory inputs to the promoter not yet defined
  4. 1994 High

    Showed that aberrant POMC processing underlies ectopic ACTH syndrome, with unprocessed precursors rather than mature ACTH as the dominant circulating species.

    Evidence Specific IRMA assays and plasma chromatography in a patient cohort

    PMID:8137518

    Open questions at the time
    • Molecular cause of processing failure in tumors not resolved
    • Convertase identity not directly assayed here
  5. 2000 Medium

    Demonstrated that cell-specific POMC processing depends on differential PC1 and PC2 expression co-localized with the peptide products, explaining tissue-specific peptide output.

    Evidence In situ hybridization and immunohistochemistry in murine skin

    PMID:10858267

    Open questions at the time
    • Causal requirement for each convertase not shown by genetic deletion
    • Quantitative contribution to each peptide undefined
  6. 2001 High

    Established leptin's electrophysiological action on arcuate POMC neurons, identifying direct cation-channel depolarization plus reduced GABAergic inhibition as the basis of leptin-driven activation.

    Evidence Patch-clamp electrophysiology on GFP-tagged POMC neurons in transgenic mice

    PMID:11373681

    Open questions at the time
    • Molecular identity of the cation channel not specified here
    • Downstream signaling to Pomc transcription not addressed
  7. 2005 Medium

    Demonstrated a local extra-pituitary CRH-POMC-corticosteroid axis in skin, with CRH driving POMC/ACTH/corticosterone output in dermal fibroblasts via cAMP.

    Evidence cAMP, mRNA, protein, and hormone assays in fibroblast and keratinocyte cultures; local co-expression by in situ RT-PCR/LCM

    PMID:11511529 PMID:15833364

    Open questions at the time
    • Physiological significance of cutaneous POMC in vivo unclear
    • Convertase processing in skin fibroblasts not detailed
  8. 2008 High

    Identified a positive transcriptional regulator of POMC, showing an RXR-α/LXR-α heterodimer activates the proximal promoter and raises ACTH/corticosterone output.

    Evidence EMSA, ChIP, luciferase reporter, siRNA knockdown, in vivo LXR agonist treatment

    PMID:19036902

    Open questions at the time
    • Endogenous ligand context not defined
    • Interaction with repressive nGRE machinery unresolved
  9. 2010 High

    Defined intracellular phosphatase and kinase control of POMC neuron leptin/insulin signaling, with PTP1B/SHP2 and PDK-1/FoxO1 regulating Pomc expression and energy balance.

    Evidence POMC neuron-specific conditional knockouts and FoxO1 transgenics with metabolic and molecular readouts

    PMID:20103739 PMID:20160350

    Open questions at the time
    • Direct transcriptional targets of FoxO1 on the Pomc promoter not mapped here
    • Integration of phosphatase signals with channel activity unclear
  10. 2013 High

    Provided human genetic proof that the R8 residue of the HFRW motif is essential for melanocortin peptide receptor activation, as the p.R8C mutation yields immunoreactive but bioinactive ACTH and α-MSH.

    Evidence Exome/Sanger sequencing plus synthetic peptide binding and cAMP assays in MC1R/MC2R/MC4R cells

    PMID:23293326

    Open questions at the time
    • Structural basis of R8 contribution not resolved
    • Effect on β-endorphin signaling not tested
  11. 2014 Medium

    Established epigenetic control of Pomc, showing CpG methylation represses transcription via MeCP2/HDAC2/DNMT1 and that early-life stress alters this mark.

    Evidence Bisulfite sequencing and ChIP in pituitary tissue and AtT20 cells

    PMID:24506071

    Open questions at the time
    • Mechanism linking stress to methylation change not defined
    • Single cell-line ChIP validation
  12. 2015 High

    Revealed peptide-selective output and developmental scope of POMC cells: CB1R selectively releases β-endorphin to drive feeding, and POMC progenitors give rise to reproductive Kiss1 neurons.

    Evidence DREADD chemogenetics, peptide-specific release measurement, naloxone pharmacology, and Cre/loxP lineage tracing in mice

    PMID:25707796 PMID:25855171

    Open questions at the time
    • Mechanism of differential vesicular sorting of β-endorphin vs α-MSH not defined
    • Functional role of POMC-derived Kiss1 neurons in adult reproduction not fully tested
  13. 2016 High

    Expanded the regulatory network controlling Pomc, identifying GPR45-JAK/STAT input, ER stress sensing via IRE1α, and Tpit/Pitx1-independent E2F1 activation in ectopic tumors.

    Evidence Knockout mouse phenotyping, pathway analysis, pharmacological rescue, promoter reporter/ChIP/xenograft studies

    PMID:27500489 PMID:27935805 PMID:28028078

    Open questions at the time
    • Direct GPR45 ligand and coupling to STAT not resolved
    • Crosstalk between ER stress and transcription unmapped
  14. 2017 High

    Defined the molecular effectors of POMC neuron excitability and metabolic responsiveness, including TrpC5 channels for leptin/serotonin responses, glucocorticoid repression through NeuroD1, and bidirectional control by mitochondrial fission and fusion.

    Evidence Neuron-specific conditional knockouts, electrophysiology, EM, ROS measurement, promoter mutagenesis/ChIP, and DIO/microglia models

    PMID:28099839 PMID:28190775 PMID:28406939 PMID:28489068

    Open questions at the time
    • How mitochondrial morphology couples to firing not fully mechanistic
    • Integration of NeuroD1 with nGRE repression unresolved
  15. 2018 High

    Established ER quality control and additional signaling control of POMC, showing Sel1L-Hrd1 ERAD prevents POMC aggregation, TCPTP restrains insulin signaling, and SGK1/FOXO3 mediates glucocorticoid-induced adiposity.

    Evidence Neuron-specific knockouts, ubiquitination/fractionation biochemistry, disease-mutant analysis, clamp studies, and pharmacological rescue

    PMID:29321171 PMID:29457782 PMID:30230471

    Open questions at the time
    • Determinants of which nascent POMC is routed to ERAD vs secretion not defined
    • Connection of FOXO3 to direct Pomc promoter occupancy not shown
  16. 2019 High

    Defined receptor-trafficking control of POMC neuron signaling via the BBSome, which delivers 5-HT2CR to the surface and NPY2R to cilia, linking ciliary trafficking to satiety signaling.

    Evidence POMC neuron-specific Bbs1 KO with flow cytometry, calcium imaging, electrophysiology, and pharmacological challenge

    PMID:31127052

    Open questions at the time
    • Full repertoire of BBSome-trafficked GPCRs in POMC neurons unknown
    • Direct effect on POMC peptide output not measured
  17. 2020 Medium

    Connected arcuate POMC output to peripheral physiology and downstream circuits, regulating adipose adiponectin via sympathetic outflow and suppressing feeding through an MC4R-dependent ARC→medial amygdala projection.

    Evidence ArcPomc mutant mice, melanocortin and adrenergic pharmacology, viral tracing, and channelrhodopsin optogenetics with MC4R antagonism

    PMID:32244188 PMID:33250721

    Open questions at the time
    • Identity of melanocortin receptor mediating sympathetic adiponectin control incompletely defined
    • Relative contribution of MeA circuit to overall feeding control unquantified
  18. 2021 High

    Resolved POMC neuron heterogeneity and additional metabolic sensing, defining non-overlapping Lepr/Glp1r and GABAergic/glutamatergic subpopulations, mTORC1 control of neurotransmitter balance, lactate sensing via astrocytic HCAR1, mitohormesis through Crif1, and NF-κB repression of peripheral Pomc in diabetes.

    Evidence Intersectional genetics, translational profiling, electrophysiology, chemogenetics/optogenetics, pharmacology, and ChIP across multiple studies

    PMID:33462216 PMID:33535098 PMID:34002087 PMID:34644574 PMID:34737351

    Open questions at the time
    • Functional division of labor among subpopulations incompletely mapped
    • Mechanism coupling mitoribosomal stress to peptide selection not defined
  19. 2024 Medium

    Identified new molecular regulators of POMC neuron signaling and peptide synthesis, with AZGP1 stabilizing AGK to amplify leptin-JAK2-STAT3 signaling and Fam172a restraining histone lactylation to control PAM expression and α-MSH synthesis.

    Evidence Neuron-specific overexpression/KO mice, Co-IP, ubiquitination assays, CUT&Tag chromatin profiling, and pharmacological rescue

    PMID:38643150 PMID:39578459

    Open questions at the time
    • AZGP1-AGK interaction validated mainly by Co-IP in single lab
    • Generality of lactylation-PAM axis beyond diet-induced obesity untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse transcriptional, epigenetic, ER-quality-control, channel, and mitochondrial inputs are integrated within single POMC neuron subpopulations to determine the precise stoichiometry of α-MSH versus β-endorphin output remains unresolved.
  • No unified model linking subpopulation identity to differential peptide secretion
  • Mechanism of selective vesicular sorting of POMC-derived peptides unknown
  • In vivo interplay among competing transcriptional regulators at the Pomc promoter not reconstructed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0048018 receptor ligand activity 3
Localization
GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
MC1RMC2RMC4RPAMPCSK1PCSK2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1980 The bovine POMC (ACTH-β-LPH precursor) gene contains a single intron of ~2.2 kb that separates a small exon encoding the signal peptide from a large exon encoding most of the protein structure, including all known biologically active component peptides (ACTH, β-endorphin, MSH sequences). Genomic DNA cloning, restriction mapping, and nucleotide sequencing of bovine genomic DNA fragments Nature High 6253815
1980 The rat POMC gene coding region (from amino acid 19 to the poly-A site, encompassing all biologically active peptides including γ-MSH, ACTH, β-endorphin) contains no intervening sequences; the DNA encoding the putative γ-MSH and preceding sequence is highly conserved between rat and cow. Rat genomic DNA library cloning and DNA sequencing Nature High 6255341
1984 Glucocorticoid feedback inhibits ACTH secretion via three temporally distinct mechanisms: (1) fast feedback at the cell membrane inhibiting stimulus-secretion coupling without requiring protein synthesis; (2) intermediate feedback requiring synthesis of a corticosteroid-dependent protein that reduces stimulated ACTH release; (3) slow feedback via the classical genomic mechanism reducing pituitary POMC mRNA levels and thereby decreasing ACTH content and basal secretion. In vitro corticotrope secretion assays, in vivo pharmacology, analysis of POMC mRNA levels Endocrine reviews Medium 6323158
1989 A 543-bp fragment in the 5'-flanking region of the POMC gene is sufficient for cell-specific pituitary expression and contains a negative glucocorticoid response element (nGRE) in the proximal promoter that binds both the glucocorticoid receptor and COUP-family transcription factors in a mutually exclusive manner, mediating glucocorticoid repression of POMC transcription. DNA-mediated gene transfer into transgenic mice and tissue culture cells, DNA-binding assays with nuclear proteins Genome High 2698828
1994 Ectopic ACTH syndrome is characterized by aberrant processing of POMC such that ACTH precursors (pro-ACTH/POMC) rather than fully processed ACTH are the predominant circulating forms; chromatographic analysis confirmed ACTH precursors as the major immunoreactive species, with ACTH precursor levels correlating with cortisol whereas ACTH itself did not. Specific monoclonal-based immunoradiometric assays for ACTH and ACTH precursors, plasma chromatography under acid-dissociating conditions Clinical endocrinology High 8137518
2000 Spatiotemporal expression of POMC mRNA and processing of POMC-derived peptides (β-endorphin, ACTH, β-MSH, α-MSH) in murine skin is cell-specific and depends on the differential expression of prohormone convertases PC1 and PC2, which are present in the same cells as POMC peptides; PC1 and PC2 activities drive cell-specific differential POMC processing in the skin. In situ hybridization histochemistry and immunohistochemistry in anagen hair follicle murine skin The journal of histochemistry and cytochemistry Medium 10858267
2001 Leptin increases action potential frequency in hypothalamic POMC neurons by two mechanisms: direct depolarization through a nonspecific cation channel, and reduced inhibitory input from local orexigenic NPY/GABA neurons. Additionally, melanocortin peptides exert an autoinhibitory effect on this circuit. Electrophysiological recordings (patch-clamp) on GFP-tagged POMC neurons in transgenic mice Nature High 11373681
2001 Human skin keratinocytes and dermal fibroblasts locally express both CRH and POMC mRNA (co-expressed in the same cells), demonstrated by in situ RT-PCR combined with laser-capture microdissection, indicating local POMC production rather than uptake from the CNS. In situ reverse-transcription PCR, immunohistochemistry, laser-capture microdissection combined with RT-PCR FASEB journal Medium 11511529
2005 CRH stimulates POMC gene and protein expression, ACTH production and release, and corticosterone production in human dermal fibroblasts (but not keratinocytes) via cAMP signaling, establishing a functional CRH-POMC-corticosteroid axis in fibroblasts analogous to the HPA axis. cAMP assay, POMC gene/protein expression, ACTH ELISA, corticosterone measurement in fibroblast and keratinocyte cell cultures treated with CRH and ACTH Journal of neuroimmunology Medium 15833364
2008 LXR-α positively regulates POMC gene transcription in pituitary by binding as a RXR-α/LXR-α heterodimer to a region between -73 and -52 bp in the rat POMC promoter; LXR agonist treatment increased POMC mRNA, ACTH content, and plasma ACTH/corticosterone, and siRNA knockdown of LXR-α abolished promoter activation. EMSA, ChIP, luciferase reporter assays, siRNA knockdown, in vivo LXR agonist treatment with ACTH/corticosterone measurement Molecular endocrinology High 19036902
2010 PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance: POMC-specific PTP1B deletion improves leptin sensitivity and glucose homeostasis, while POMC-specific SHP2 deletion impairs leptin sensitivity and markedly reduces hypothalamic POMC mRNA and α-MSH peptide levels, implicating SHP2 in normal melanocortin system function. Cre-LoxP conditional knockout mice, measurement of adiposity, leptin sensitivity, energy expenditure, POMC mRNA, α-MSH peptide levels, and hyperinsulinemic-euglycemic clamp The Journal of clinical investigation High 20160350
2010 PDK-1 and FoxO1 signaling in POMC neurons regulate POMC gene transcription and food intake: POMC-neuron-specific PDK-1 knockout decreases Pomc gene expression and increases food intake/body weight; constitutively nuclear FoxO1 in POMC neurons further suppresses Pomc expression in PDK-1 KO mice, while transactivation-defective FoxO1 has no effect. POMC neuron-specific Pdk1 knockout mice; transgenic mice expressing constitutively nuclear or transactivation-defective FoxO1 in POMC neurons; food intake, body weight, and Pomc mRNA measurement American journal of physiology. Endocrinology and metabolism High 20103739
2013 POMC mutation p.R8C causes bioinactive ACTH and α-MSH: ACTH-R8C is immunoreactive but fails to bind and activate cAMP production in MC2R-expressing cells, and α-MSH-R8C fails to bind and stimulate cAMP in MC1R- and MC4R-expressing cells, demonstrating that residue R8 (within the HFRW motif) is essential for receptor binding and activation. Whole exome sequencing, Sanger sequencing, peptide synthesis, ACTH immunoradiometric assay, hormone binding assays, cAMP activation assays in cells expressing MC1R, MC2R, or MC4R The Journal of clinical endocrinology and metabolism High 23293326
2014 Early-life stress reduces DNA methylation at a critical regulatory region of the Pomc promoter in pituitary, increasing Pomc mRNA; site-specific CpG methylation of the Pomc promoter represses Pomc mRNA transcription, and methyl-CpG binding protein-2 (MeCP2) binds the distal Pomc promoter in association with HDAC2 and DNMT1 to mediate this repression. Bisulfite sequencing, promoter methylation analysis, AtT20 pituitary cell transfection, ChIP for MeCP2/HDAC2/DNMT1 at the Pomc promoter Endocrinology Medium 24506071
2015 CB1R activation selectively increases β-endorphin but not α-MSH release from hypothalamic POMC neurons; this β-endorphin release mediates CB1R-induced feeding because the opioid receptor antagonist naloxone (systemic or hypothalamic) blocks CB1R-induced hyperphagia. DREADD-mediated inhibition of POMC neurons diminishes, while activation enhances, CB1R-driven feeding. DREADD chemogenetics, hypothalamic β-endorphin and α-MSH measurement, naloxone pharmacology, mitochondrial functional assays in mice Nature High 25707796
2015 POMC-expressing progenitors in the hypothalamus give rise not only to POMC and AgRP neurons but also to Kiss1 neurons critical for puberty and reproductive function, establishing a developmental link between nutrient-sensing and reproductive neuroendocrine populations. Embryonic and adult ribosome-tagging Cre/loxP lineage tracing in mice The Journal of neuroscience Medium 25855171
2016 GPR45 regulates POMC expression via the JAK/STAT signaling pathway in a cell-autonomous manner; disruption of Gpr45 reduces POMC expression and energy expenditure, and these effects are rescued by intraventricular melanocortin agonist (melanotan-2). Piggyback insertional mutagenesis screen, Gpr45 knockout mice, POMC mRNA measurement, JAK/STAT pathway analysis, intracerebroventricular drug rescue The Journal of clinical investigation Medium 27500489
2016 IRE1α in POMC neurons is required for normal energy expenditure, thermogenesis, and glucose homeostasis; its loss elevates ER stress in POMC neurons and predisposes them to leptin and insulin resistance. POMC neuron-specific Ire1α conditional knockout mice, metabolic phenotyping (energy expenditure, thermogenesis, glucose tolerance, insulin tolerance), ER stress marker measurement Diabetes Medium 28028078
2016 E2F1 mediates ectopic POMC transcription in non-pituitary tumor cells independently of the pituitary-specific Tpit/Pitx1 factors; an E2F1 cluster binds the proximal hPOMC promoter (-42 to +68), with DNA-binding activity regulated by phosphorylation at Ser-337; E2F1/DP1 co-expression upregulates hPOMC mRNA up to 40-fold, and E2F1 inhibitors suppress ACTH in ectopic Cushing's cell lines and xenograft models. Promoter luciferase assays, ChIP, site-directed mutagenesis of E2F1 Ser-337, siRNA knockdown, xenograft mouse model with ACTH/cortisol measurement Endocrine-related cancer High 27935805
2017 TrpC5 channel subunits in POMC neurons are required for the acute anorexigenic electrophysiological and behavioral responses to leptin and serotonin 2C receptor (Ht2Cr) agonists; POMC-specific Trpc5 deletion blunts depolarization of POMC neurons by both stimuli and abolishes their anorectic effects. POMC neuron-specific and pan-neuronal Trpc5 conditional knockout mice, electrophysiology (patch-clamp), food intake measurement, glucose/insulin tolerance tests Cell reports High 28099839
2017 DRP1-mediated mitochondrial fission in POMC neurons suppresses their leptin sensitivity and glucose responsiveness; inducible deletion of DRP1 in POMC neurons increases mitochondrial size, ROS production, and neuronal activation via increased Kcnj11 (KATP channel) mRNA regulated by PPAR, improving leptin sensitivity and glucoprivic responses. Inducible POMC neuron-specific Drp1 conditional knockout (Drp1fl/fl-POMC-cre:ERT2), electron microscopy, electrophysiology, ROS measurement, qPCR, PPAR inhibition Cell metabolism High 28190775
2017 TNFα hypersecretion from persistently activated microglia in the mediobasal hypothalamus of obese mice stimulates mitochondrial ATP production and fusion in POMC neuron neurites, increasing POMC neuronal firing rates and excitability; disruption of TNFα downstream signals TNFSF11A or NDUFAB1 in the MBH reverses mitochondrial elongation and reduces obesity. Diet-induced obesity mouse model, microglial activation assays, TNFα measurement, mitochondrial morphology analysis, electrophysiology, targeted gene disruption (viral knockdown) in the MBH Nature communications Medium 28489068
2017 NeuroD1 mediates glucocorticoid-dependent repression of Pomc transcription: glucocorticoids inhibit NeuroD1 expression and the interaction of NeuroD1 with the E-box at -376/-371 of the Pomc promoter; overexpression of NeuroD1 rescues DEX-mediated inhibition of Pomc expression. Luciferase reporter assay with Pomc promoter deletion/point mutants, ChIP, qRT-PCR, NeuroD1 overexpression rescue in AtT20 cells PloS one Medium 28406939
2018 TCPTP (T-cell protein tyrosine phosphatase) in POMC neurons negatively regulates insulin receptor signaling and the proportion of POMC neurons activated by insulin; TCPTP levels increase with fasting and in diet-induced obesity, reducing insulin-induced POMC neuronal activation and POMC-mediated repression of hepatic glucose production. TCPTP-deficient POMC neuron mouse model, c-fos neuronal activation assays, hyperinsulinemic-euglycemic clamp, hepatic glucose production measurement eLife Medium 30230471
2018 SGK1/FOXO3 signaling in POMC neurons mediates glucocorticoid-induced adiposity: chronic glucocorticoid decreases SGK1 in arcuate POMC neurons; POMC-specific SGK1 knockout increases adiposity and decreases α-MSH/POMC expression via FOXO3; constitutively active SGK1 in POMC neurons prevents dexamethasone-induced adiposity. ICV α-MSH or FOXO3 knockdown rescue the metabolic phenotype. POMC neuron-specific SGK1 conditional KO and overexpression mice, POMC/α-MSH mRNA/protein measurement, ICV injection of α-MSH, adenoviral FOXO3 knockdown, body composition analysis Diabetes High 29321171
2018 The Sel1L-Hrd1 ER-associated degradation (ERAD) complex in POMC neurons targets a fraction of nascent POMC for ubiquitination and proteasomal degradation, preventing accumulation of misfolded/aggregated POMC and enabling normal POMC processing and secretion. POMC-specific Sel1L deficiency causes POMC ER retention and hyperphagia-driven age-associated obesity. The disease-associated POMC-C28F mutant evades ERAD and aggregates due to an unpaired cysteine thiol at position 50. POMC neuron-specific Sel1L knockout mice, ubiquitination assays, proteasome inhibition, ER fractionation, co-immunoprecipitation, POMC-C28F mutant biochemical characterization The Journal of clinical investigation High 29457782
2019 The BBSome complex in POMC neurons regulates trafficking of G protein-coupled receptors including serotonin 5-HT2CR to the plasma membrane and NPY2R to cilia; Bbs1 deletion in POMC neurons reduces cell surface 5-HT2CR expression, interferes with serotonin-evoked calcium signaling and membrane depolarization, and causes obesity with hyperphagia. POMC neuron-specific Bbs1 conditional KO mice, flow cytometry for receptor surface expression, calcium imaging, electrophysiology, lorcaserin anorectic response testing, late endosome staining Diabetes High 31127052
2019 MCH reduces POMC neuronal activity and POMC expression through SIRT1/FoxO1 signaling in the hypothalamic arcuate nucleus; the metabolic (hyperphagia, adiposity, glucose intolerance) actions of MCH are abolished in mice lacking SIRT1 specifically in POMC neurons, and are independent of AgRP neurons. Pharmacological MCH injection, POMC neuron-specific SIRT1 knockout mice, chemogenetic AgRP neuron stimulation, POMC electrophysiology, POMC mRNA measurement Diabetes Medium 31530579
2020 Hypothalamic arcuate POMC neurons regulate circulating adiponectin via sympathetic outflow to adipose tissue: ArcPomc-deficient mice have elevated adiponectin despite obesity, which is reversed by genetic restoration of Pomc in the ARC or by melanocortin receptor activation (melanotan II), and is mediated through norepinephrine-dependent adrenergic signaling in adipose tissue. ArcPomc-/- mice, genetic Pomc restoration, ICV/peripheral melanotan II, norepinephrine and propranolol injections, adiponectin ELISA, sympathetic marker measurement in adipose tissue Molecular metabolism Medium 32244188
2020 Optogenetic activation of the ARCPOMC→MeA neural circuit (POMC axon projections to MC4R- and estrogen receptor-α-expressing neurons in the medial amygdala) reduces short-term food intake, and this anorectic effect is blocked by the MC4R antagonist SHU9119. Anterograde and retrograde viral tracing, double immunohistochemistry, channelrhodopsin-2 optogenetics, MC4R antagonist pharmacology Frontiers in neural circuits Medium 33250721
2021 POMC neurons in the arcuate nucleus are depolarized by lactate through two mechanisms: (1) activation of HCAR1 receptors located on astrocytes (not POMC neurons themselves), acting as an intercellular signaling relay (blocked by pertussis toxin), and (2) direct intracellular action via lactate transporters in a subset of POMC neurons (blocked by 4-CIN). Conditional genetic labeling of POMC neurons, whole-cell patch-clamp recordings, HCAR1 agonist (3Cl-HBA), pertussis toxin (Gαi/o inhibitor), 4-CIN (lactate transporter blocker), immunohistochemistry for HCAR1 localization Scientific reports Medium 34737351
2021 Functionally distinct subpopulations of POMC neurons defined by leptin receptor (Lepr) and GLP-1 receptor (Glp1r) expression are largely non-overlapping, have distinct basic electrophysiological properties, specific anatomical distribution within the arcuate nucleus, differentially express metabolic hormone receptors, and differ in their ability to suppress feeding. Intersectional Cre/Dre-dependent recombination mouse models, translational profiling, electrophysiology, chemogenetics, feeding assays Nature neuroscience High 34002087
2021 mTORC1 activity in POMC neurons orchestrates the balance between POMC/GABAergic and POMC/glutamatergic subpopulations: mTORC1 blockade decreases α-MSH production, recruits POMC/GABAergic neurotransmission (restrained by CB1R signaling), simultaneously activates GABAergic POMC neurons and inhibits glutamatergic POMC neurons, causing hyperphagia. Conditional mTORC1 mutagenesis in POMC neurons, α-MSH measurement, chemogenetics, electrophysiology, optogenetics, CB1R pharmacology Cell reports High 34644574
2021 Mild mitoribosomal stress (Crif1 heterodeficiency) in POMC neurons increases β-endorphin and mitochondria-encoded peptide MOTS-c expression; central administration of either MOTS-c or β-endorphin recapitulates adipose tissue UPRmt and thermogenesis, identifying these POMC neuron-derived factors as mediators of exercise-induced high-turnover metabolism. POMC neuron-specific Crif1 homo- and heterodeficient mice, central peptide injection, adipose tissue UPRmt and thermogenesis measurement, running exercise paradigm Cell metabolism Medium 33535098
2021 In diabetic mice, POMC-mediated antinociception in sensory neurons is lost because NF-κB p50 subunit binding to the Pomc promoter is increased, repressing Pomc transcription; additionally, μ-opioid receptor (MOR) undergoes lysosomal degradation. Viral overexpression of POMC and MOR in sensory ganglia rescues the neuropathic phenotype. Streptozotocin diabetic mouse model, ChIP for NF-κB p50 at Pomc promoter, POMC protein/mRNA quantification in peripheral nerves, MOR lysosomal degradation assay, viral overexpression rescue Nature communications Medium 33462216
2024 AZGP1 in POMC neurons enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block AGK's ubiquitination-dependent degradation; POMC neuron-specific Azgp1 overexpression increases STAT3 phosphorylation and POMC neuronal excitability, reducing food intake and improving metabolic parameters. POMC neuron-specific Azgp1 overexpression and inducible KO mice, Co-IP for AZGP1-AGK interaction, ubiquitination assays, STAT3 phosphorylation (western blot), patch-clamp electrophysiology Nature communications Medium 38643150
2024 Fam172a in POMC neurons acts as a negative regulator of histone lactylation (H4K12la): POMC neuron-specific Fam172a deletion increases H4K12la, activates glycolysis, and upregulates peptidylglycine α-amidating monooxygenase (PAM) expression, increasing α-MSH synthesis and protecting against diet-induced obesity; pharmacological inhibition of lactate production abolishes the anti-obesity effect. POMC neuron-specific Fam172a KO and overexpression mice, RNA-seq, CUT&Tag chromatin profiling for H4K12la, PAM expression analysis, α-MSH measurement, lactate inhibitor treatment Nature communications Medium 39578459

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 1845 11373681
1984 Corticosteroid inhibition of ACTH secretion. Endocrine reviews 1111 6323158
2015 Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 336 25707796
2012 Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO reports 324 23146889
2005 NPP-type ectophosphodiesterases: unity in diversity. Trends in biochemical sciences 311 16125936
1980 Most of the coding region of rat ACTH beta--LPH precursor gene lacks intervening sequences. Nature 289 6255341
2008 Dissociation of ACTH and glucocorticoids. Trends in endocrinology and metabolism: TEM 266 18394919
2009 Hormone and glucose signalling in POMC and AgRP neurons. The Journal of physiology 198 19770186
2018 POMC: The Physiological Power of Hormone Processing. Physiological reviews 184 30156493
2010 PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. The Journal of clinical investigation 170 20160350
1978 Behavioral and electrophysiological effects of peptides related to lipotropin (beta-LPH). The Journal of pharmacology and experimental therapeutics 140 204766
2010 The ectopic ACTH syndrome. Reviews in endocrine & metabolic disorders 138 20544290
2021 Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nature neuroscience 132 34002087
2007 Ectopic ACTH syndrome. Arquivos brasileiros de endocrinologia e metabologia 120 18209859
2005 CRH stimulates POMC activity and corticosterone production in dermal fibroblasts. Journal of neuroimmunology 116 15833364
2000 Implications of proopiomelanocortin (POMC) mutations in humans: the POMC deficiency syndrome. Trends in endocrinology and metabolism: TEM 110 10652501
2008 Effects of non-human species irradiation after the Chernobyl NPP accident. Environment international 102 18234336
2018 Insulin regulates POMC neuronal plasticity to control glucose metabolism. eLife 101 30230471
2017 TNFα drives mitochondrial stress in POMC neurons in obesity. Nature communications 100 28489068
2006 Proopiomelanocortin (POMC): the cutaneous roles of its melanocortin products and receptors. Clinical and experimental dermatology 98 16681590
2014 Early-life stress reduces DNA methylation of the Pomc gene in male mice. Endocrinology 97 24506071
2011 Evolution of POMC: origin, phylogeny, posttranslational processing, and the melanocortins. Annals of the New York Academy of Sciences 97 21388402
2002 Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice. American journal of physiology. Regulatory, integrative and comparative physiology 94 12376393
2016 Hypothalamic AMPK-induced autophagy increases food intake by regulating NPY and POMC expression. Autophagy 92 27533078
2001 In situ expression of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) genes in human skin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 91 11511529
2017 TrpC5 Mediates Acute Leptin and Serotonin Effects via Pomc Neurons. Cell reports 87 28099839
1994 ACTH precursors characterize the ectopic ACTH syndrome. Clinical endocrinology 87 8137518
2018 Hypothalamic ER-associated degradation regulates POMC maturation, feeding, and age-associated obesity. The Journal of clinical investigation 79 29457782
2017 DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons. Cell metabolism 79 28190775
2021 Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism. Cell metabolism 74 33535098
2018 Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Molecular metabolism 74 30292523
2015 Fertility-regulating Kiss1 neurons arise from hypothalamic POMC-expressing progenitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 74 25855171
2016 60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH. Journal of molecular endocrinology 72 26793988
2015 60 YEARS OF POMC: From POMC and α-MSH to PAM, molecular oxygen, copper, and vitamin C. Journal of molecular endocrinology 71 26667899
2010 DNA methylation of the POMC gene promoter is associated with craving in alcohol dependence. Journal of neural transmission (Vienna, Austria : 1996) 68 20191296
2012 GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility. American journal of physiology. Endocrinology and metabolism 67 22829581
2002 An ACTH- and ATP-regulated background K+ channel in adrenocortical cells is TREK-1. The Journal of biological chemistry 67 12368289
2003 Adrenocortical zonation and ACTH. Microscopy research and technique 66 12768537
1980 The protein-coding sequence of the bovine ACTH-beta-LPH precursor gene is split near the signal peptide region. Nature 62 6253815
2018 Amylin Selectively Signals Onto POMC Neurons in the Arcuate Nucleus of the Hypothalamus. Diabetes 59 29467172
2015 Pro-Opiomelanocortin (POMC) Neurones, POMC-Derived Peptides, Melanocortin Receptors and Obesity: How Understanding of this System has Changed Over the Last Decade. Journal of neuroendocrinology 59 25872650
2010 PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake. American journal of physiology. Endocrinology and metabolism 58 20103739
2016 60 YEARS OF POMC: Melanocortin receptors: evolution of ligand selectivity for melanocortin peptides. Journal of molecular endocrinology 57 26792827
1999 ACTH resistance syndromes. Journal of pediatric endocrinology & metabolism : JPEM 56 10698592
1995 Ectopic ACTH syndrome. The Journal of steroid biochemistry and molecular biology 55 7626446
1977 Lung tumours and ACTH production. Clinical endocrinology 55 191221
2005 Inherited ACTH insensitivity illuminates the mechanisms of ACTH action. Trends in endocrinology and metabolism: TEM 54 16271481
2019 The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors. Diabetes 53 31127052
2019 Epigenetic regulation of POMC; implications for nutritional programming, obesity and metabolic disease. Frontiers in neuroendocrinology 53 31344387
2012 The neuroendocrine circuitry controlled by POMC, MSH, and AGRP. Handbook of experimental pharmacology 52 22249810
1999 The skin POMC system (SPS). Leads and lessons from the hair follicle. Annals of the New York Academy of Sciences 52 10816666
2022 Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide. Journal of the Endocrine Society 48 35528826
2000 Linkage and association studies between the proopiomelanocortin (POMC) gene and obesity in caucasian families. Diabetologia 43 11151766
2021 Functional heterogeneity of POMC neurons relies on mTORC1 signaling. Cell reports 41 34644574
2016 Ire1α in Pomc Neurons Is Required for Thermogenesis and Glycemia. Diabetes 41 28028078
1989 Tissue-specific activity of the pro-opiomelanocortin (POMC) gene and repression by glucocorticoids. Genome 41 2698828
2008 Early embryonic requirement for nucleoporin Nup35/NPP-19 in nuclear assembly. Developmental biology 40 19146848
1980 Secretion of ACTH, LPH and beta-endophin from human pituitary tumours in vitro. Clinical endocrinology 40 6254699
2013 Bioinactive ACTH causing glucocorticoid deficiency. The Journal of clinical endocrinology and metabolism 39 23293326
2011 Early onset obesity and adrenal insufficiency associated with a homozygous POMC mutation. International journal of pediatric endocrinology 39 21860632
2000 Spatiotemporal expression, distribution, and processing of POMC and POMC-derived peptides in murine skin. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 39 10858267
2021 Lactate activates hypothalamic POMC neurons by intercellular signaling. Scientific reports 36 34737351
2019 MCH Regulates SIRT1/FoxO1 and Reduces POMC Neuronal Activity to Induce Hyperphagia, Adiposity, and Glucose Intolerance. Diabetes 35 31530579
2006 The genetics of ACTH resistance syndromes. Best practice & research. Clinical endocrinology & metabolism 35 17161331
2016 Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity. The Journal of clinical investigation 34 27500489
2013 Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways. The Journal of endocrinology 34 24134870
1974 ACTH antagonists. Proceedings of the National Academy of Sciences of the United States of America 34 4359333
2014 Clinical utility of plasma POMC and AgRP measurements in the differential diagnosis of ACTH-dependent Cushing's syndrome. The Journal of clinical endocrinology and metabolism 33 25013995
2005 Circumventing central leptin resistance: lessons from central leptin and POMC gene delivery. Peptides 32 16274846
2005 Nucleoporins NPP-1, NPP-3, NPP-4, NPP-11 and NPP-13 are required for proper spindle orientation in C. elegans. Developmental biology 31 16325795
2018 POMC Neurons: Feeding, Energy Metabolism, and Beyond. Advances in experimental medicine and biology 30 30390283
2016 ACTH Antagonists. Frontiers in endocrinology 30 27547198
2018 SGK1/FOXO3 Signaling in Hypothalamic POMC Neurons Mediates Glucocorticoid-Increased Adiposity. Diabetes 29 29321171
2016 E2F1-mediated human POMC expression in ectopic Cushing's syndrome. Endocrine-related cancer 29 27935805
2013 Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons. PloS one 28 24204898
2000 Pro-opiomelanocortin (POMC) deficiency and peripheral melanocortins in obesity. Nutrition reviews 27 10885325
2024 AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation. Nature communications 26 38643150
2015 60 YEARS OF POMC: POMC: an evolutionary perspective. Journal of molecular endocrinology 25 26671895
2013 ACTH resistance: genes and mechanisms. Endocrine development 25 23392095
2020 Activation of the ARCPOMC→MeA Projection Reduces Food Intake. Frontiers in neural circuits 24 33250721
1996 The ACTH receptor. Bailliere's clinical endocrinology and metabolism 24 8734450
2021 Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy. Nature communications 23 33462216
2016 ACTH Action on StAR Biology. Frontiers in neuroscience 23 27999527
2015 60 YEARS OF POMC: The proopiomelanocortin gene: discovery, deletion and disease. Journal of molecular endocrinology 23 26643913
1995 Adrenocorticotropic hormone (ACTH) increases the expression of its own receptor gene. Endocrine journal 23 8556053
2021 The Impact of Recent Developments in Electrochemical POC Sensor for Blood Sugar Care. Frontiers in chemistry 22 34395386
2020 Hypothalamic POMC deficiency increases circulating adiponectin despite obesity. Molecular metabolism 22 32244188
2008 Liver X receptor-alpha regulates proopiomelanocortin (POMC) gene transcription in the pituitary. Molecular endocrinology (Baltimore, Md.) 22 19036902
2022 Involvement of POMC neurons in LEAP2 regulation of food intake and body weight. Frontiers in endocrinology 21 36387867
2019 Selective Restoration of Pomc Expression in Glutamatergic POMC Neurons: Evidence for a Dynamic Hypothalamic Neurotransmitter Network. eNeuro 21 30957016
2021 Hypothalamic Expression of Neuropeptide Y (NPY) and Pro-OpioMelanoCortin (POMC) in Adult Male Mice Is Affected by Chronic Exposure to Endocrine Disruptors. Metabolites 20 34207679
2015 Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression. PloS one 20 26714014
2021 Barbadin Potentiates Long-Term Effects of Lorcaserin on POMC Neurons and Weight Loss. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 34031163
2017 Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid. PloS one 19 28406939
2005 Expression of AgRP, NPY, POMC and CART in human fetal and adult hippocampus. Neuropeptides 19 15885775
2018 Hypothalamic POMC or MC4R deficiency impairs counterregulatory responses to hypoglycemia in mice. Molecular metabolism 18 30503832
2003 ACTH and adrenocortical gap junctions. Microscopy research and technique 18 12768538
1996 Regulation of sucrase and lactase in Caco-2 cells: relationship to nuclear factors SIF-1 and NF-LPH-1. The American journal of physiology 18 8897892
2023 Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use. Genetics in medicine : official journal of the American College of Medical Genetics 17 37092539
2024 Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance. Nature communications 16 39578459

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