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Proopiomelanocortin
Proopiomelanocortin
Proopiomelanocortin
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POMC
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPOMC, POC, proopiomelanocortin, OBAIRH, LPH, CLIP, ACTH, NPP, MSH
External IDsOMIM: 176830; MGI: 97742; HomoloGene: 723; GeneCards: POMC; OMA:POMC - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5443

18976

Ensembl

ENSG00000115138

ENSMUSG00000020660

UniProt

P01189

P01193

RefSeq (mRNA)

NM_000939
NM_001035256
NM_001319204
NM_001319205

NM_008895
NM_001278581
NM_001278582
NM_001278583
NM_001278584

RefSeq (protein)

NP_000930
NP_001030333
NP_001306133
NP_001306134

NP_001265510
NP_001265511
NP_001265512
NP_001265513
NP_032921

Location (UCSC)Chr 2: 25.16 – 25.17 MbChr 12: 4 – 4.01 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Opioids neuropeptide
Identifiers
SymbolOp_neuropeptide
PfamPF08035
InterProIPR013532
PROSITEPDOC00964
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation.[5] POMC is part of the central melanocortin system.

Gene

[edit]

The POMC gene is located on chromosome 2p23.3. This gene encodes a 285-amino acid polypeptide hormone precursor that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases.

Tissue distribution

[edit]

The POMC gene is expressed in both the anterior and intermediate lobes of the pituitary gland. Its protein product is primarily synthesized by corticotropic cells in the anterior pituitary, but it is also produced in several other tissues:

Function

[edit]

POMC is cut (cleaved) to give rise to multiple peptide hormones. Each of these peptides is packaged in large dense-core vesicles that are released from the cells by exocytosis in response to appropriate stimulation:[citation needed]

Post-translational modifications

[edit]

The POMC gene encodes a 285-amino acid polypeptide precursor that undergoes extensive, tissue-specific post-translational processing. This processing is primarily mediated by subtilisin-like prohormone convertases, which cleave the precursor at specific basic amino acid sequences—typically Arg-Lys, Lys-Arg, or Lys-Lys.

In many tissues, four primary cleavage sites are utilized, resulting in the production of two major bioactive peptides: adrenocorticotrophin (ACTH), which is essential for normal steroidogenesis and adrenal gland maintenance, and β-lipotropin. However, the POMC precursor contains at least eight potential cleavage sites, and depending on the tissue type and the specific convertases expressed, it can be processed into up to ten biologically active peptides with diverse functions.

Key processing enzymes include prohormone convertase 1 (PC1), prohormone convertase 2 (PC2), carboxypeptidase E (CPE), peptidyl α-amidating monooxygenase (PAM), N-acetyltransferase (N-AT), and prolylcarboxypeptidase (PRCP).[citation needed]

In addition to proteolytic cleavage, POMC processing involves other post-translational modifications such as glycosylation and acetylation. The specific pattern of cleavage and modification is tissue-dependent. For example, in the hypothalamus, placenta, and epithelium, all cleavage sites may be active, generating peptides involved in pain modulation, energy homeostasis, immune responses, and melanocyte stimulation. These peptides include multiple melanotropins, lipotropins, and endorphins, many of which are derived from the larger ACTH and β-lipotropin peptides.[citation needed]

Derivatives

[edit]
proopiomelanocortin derivatives
POMC
     
γ-MSH ACTH β-lipotropin
         
  α-MSH CLIP γ-lipotropin β-endorphin
       
    β-MSH  

The large POMC precursor is the source of numerous biologically active peptides, which are produced through sequential enzymatic cleavage. These include:

N-Terminal Peptide of Proopiomelanocortin (NPP, or pro-γ-MSH) α-Melanotropin (α-Melanocyte-Stimulating Hormone, or α-MSH) β-Melanotropin (β-MSH) γ-Melanotropin (γ-MSH) 𝛿-Melanocyte-Stimulating Hormone (𝛿-MSH), found in sharks[10] ε-Melanocyte-Stimulating Hormone (ε-MSH), present in some teleost fish[11] Corticotropin (Adrenocorticotropic Hormone, or ACTH) Corticotropin-like Intermediate Peptide (CLIP) β-Lipotropin (β-LPH) Gamma Lipotropin (γ-LPH) β-Endorphin [Met]Enkephalin Although the first five amino acids of β-Endorphin are identical to [Met]enkephalin,[12] β-Endorphin is not generally believed to be a precursor of [Met]enkephalin.[citation needed] Instead, [Met]enkephalin is produced independently from its own precursor, proenkephalin A.

The production of β-MSH occurs in humans, but not in mice or rats, due to the absence of the necessary cleavage site in the rodent POMC sequence.

Regulation by the photoperiod

[edit]

The levels of proopiomelanocortin (pomc) are regulated indirectly in some animals by the photoperiod. It is referred to[clarification needed] the hours of light during a day and it changes across the seasons. Its regulation depends on the pathway of thyroid hormones that is regulated directly by the photoperiod. An example are the siberian hamsters who experience physiological seasonal changes dependent on the photoperiod. During spring in this species, when there is more than 13 hours of light per day, iodothyronine deiodinase 2 (DIO2) promotes the conversion of the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3) through the removal of an iodine atom on the outer ring. It allows T3 to bind to the thyroid hormone receptor (TR), which then binds to thyroid hormone response elements (TREs) in the DNA sequence. The pomc proximal promoter sequence contains two thyroid-receptor 1b (Thrb) half-sites: TCC-TGG-TGA and TCA-CCT-GGA indicating that T3 may be capable of directly regulating pomc transcription. For this reason during spring and early summer, the level of pomc increases due to the increased level of T3.[13]

However, during autumn and winter, when there is less than 13 hours of light per day, iodothyronine desiodinase 3 removes an iodine atom which converts thyroxine to the inactive reverse triiodothyronine (rT3), or which converts the active triiodothyronine to diiodothyronine (T2). Consequently, there is less T3 and it blocks the transcription of pomc, which reduces its levels during these seasons.[14]

Regulation of proopiomelanocortin by the photoperiod and thyroid hormones

Influences of photoperiods on relevant similar biological endocrine changes that demonstrate modifications of thyroid hormone regulation in humans have yet to be adequately documented.

Clinical significance

[edit]

Mutations in the POMC gene have been associated with early-onset obesity,[15] adrenal insufficiency, and red hair pigmentation.[16]

In cases of primary adrenal insufficiency, decreased cortisol production leads to compensatory overproduction of pituitary ACTH through feedback mechanisms. Because ACTH is co-produced with α-MSH and γ-MSH from POMC, this overproduction can result in hyperpigmentation.[17]

A specific genetic polymorphism in the POMC gene is associated with elevated fasting insulin levels, but only in obese individuals. The melanocortin signaling pathway may influence glucose metabolism in the context of obesity, indicating a possible gene–environment interaction. Thus, POMC variants may contribute to the development of polygenic obesity and help explain the connection between obesity and type 2 diabetes.[18]

Increased circulating levels of POMC have also been observed in patients with sepsis.[19] While the clinical implications of this finding are still under investigation, animal studies have shown that infusion of hydrocortisone in septic mice suppresses ACTH (a downstream product of POMC) without reducing POMC levels themselves.[20]

Drug target

[edit]

POMC is a pharmacological target for obesity treatment. The combination drug naltrexone/bupropion acts on hypothalamic POMC neurons to reduce appetite and food intake.[21]

In rare cases of POMC deficiency, treatment with setmelanotide, a selective melanocortin-4 receptor agonist, has been effective. Two individuals with confirmed POMC deficiency showed clinical improvement following this therapy.[22]

Dogs

[edit]

A deletion mutation common in Labrador Retriever and Flat-coated Retriever dogs is associated with increased interest in food and subsequent obesity.[23]

Interactions

[edit]

Proopiomelanocortin has been shown to interact with melanocortin 4 receptor.[24][25] The endogenous agonists of melanocortin 4 receptor include α-MSH, β-MSH, γ-MSH, and ACTH. The fact that these are all cleavage products of POMC should suggest likely mechanisms of this interaction.[citation needed]

See also

[edit]

References

[edit]

Further reading

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Proopiomelanocortin

View on Grokipedia
from Grokipedia
Proopiomelanocortin (POMC) is a 241-amino-acid polypeptide precursor encoded by the POMC gene, which undergoes extensive tissue-specific posttranslational processing to generate multiple bioactive , including adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), , β-lipotropin (β-LPH), β-MSH, γ-MSH, and corticotropin-like intermediate peptide (CLIP). The POMC gene is located on the short arm of human at position 2p23 and consists of three s separated by two introns, with translation initiating in exon 2 to produce the precursor protein that includes distinct domains for the N-terminal , ACTH, and β-LPH regions. Processing of POMC occurs primarily within secretory granules through cleavage by prohormone convertases such as PC1/3 and PC2 at dibasic sites, followed by modifications including amidation, , and carboxypeptidase activity, resulting in different profiles depending on the tissue; for example, in the , it yields ACTH and β-LPH, while in the and intermediate pituitary, it produces α-MSH and β-endorphin. POMC is expressed in various tissues, with prominent sites including the anterior and intermediate lobes of the pituitary gland, neurons in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarius in the brainstem, keratinocytes and melanocytes in the skin, and to a lesser extent in the placenta, adrenal glands, heart, and testes. Physiologically, POMC-derived peptides mediate diverse functions through interactions with melanocortin receptors (MC1R–MC5R) and opioid receptors; ACTH primarily regulates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating cortisol release from the adrenal cortex and promoting adrenal growth, while α-MSH acts via MC4R to suppress appetite and maintain energy homeostasis in the hypothalamus. Additionally, binds to μ-opioid receptors to provide analgesia and modulate stress responses, α-MSH and ACTH influence skin pigmentation via MC1R, and γ-MSH contributes to regulation and through MC3R. Mutations in the POMC gene or defects in its processing enzymes lead to disorders such as early-onset , , pigmentation, and , underscoring its critical role in metabolic, endocrine, and pigmentation pathways.

Genetics and Molecular Structure

Gene Location and Organization

The human POMC gene is located on the short arm of at the cytogenetic band 2p23.3. This positioning is highly conserved across mammalian species, with orthologous genes found on syntenic regions in (e.g., ) and other vertebrates, reflecting evolutionary preservation of its regulatory architecture. The gene spans approximately 7.8 kb and consists of three exons separated by two large introns. Exon 1 is non-coding, comprising the 5' untranslated region (UTR) and harboring key promoter elements. Exon 2 encodes the signal peptide and the N-terminal portion of the prohormone, including the translation initiation site. Exon 3 contains the majority of the coding sequence for the core polyprotein precursor, along with the 3' UTR. The promoter region upstream of exon 1 includes multiple regulatory elements that control POMC transcription. Notably, response elements (GREs) mediate by , binding the to repress expression, while cAMP response elements (CREs) facilitate activation via cAMP-dependent pathways, such as those triggered by (CRH). These elements are critical for tissue-specific and stimulus-responsive regulation in the pituitary and . Certain structural variants in the POMC gene influence transcription. A prominent example is an Alu element-associated hypermethylation variant in the promoter region, which correlates with increased and reduced POMC expression, contributing to risk in humans. Other polymorphisms, such as rs2071345 in the upstream region, have been linked to altered transcriptional efficiency and associated phenotypes like .

Protein Primary Structure

Pro-opiomelanocortin (POMC) is a precursor protein in humans consisting of 267 in its prepro form, including a 26-residue N-terminal that directs the protein to the secretory pathway and is cleaved upon entry into the , yielding a mature POMC of 241 . The primary amino acid sequence of human POMC, encoded by the POMC gene on , features a linear polypeptide chain with distinct regions that serve as precursors for multiple bioactive peptides. The protein's structure includes an N-terminal region encompassing pro-gamma-melanocyte-stimulating hormone (pro-γ-MSH, residues 27–102 post-signal cleavage), followed by a joining peptide (residues 103–137) that links it to the central core. The central region contains sequences for (ACTH, residues 138–176), α-melanocyte-stimulating hormone (α-MSH, residues 138–150 within ACTH), β-lipotropin (β-LPH, residues 177–267), and (residues 237–267 within β-LPH). These domains are organized such that the N-terminal and joining peptide regions are encoded primarily by exon 2 of the POMC gene, while the central and C-terminal sequences span exons 2 and 3. Specific cleavage sites within the POMC sequence are marked by dibasic residue pairs, such as Lys-Arg and Lys-Lys, which are recognized by prohormone convertases PC1/3 and PC2 for subsequent processing into mature peptides; examples include the Arg49-Lys50 site in the N-terminal region and Lys-Lys pairs flanking ACTH and β-LPH. These sites ensure tissue-specific proteolytic maturation but are inherent to the primary structure of the intact precursor. Post-translational modifications on the POMC precursor itself include N-glycosylation at residue 47 (Asn47) in the pro-γ-MSH domain, which contributes to proper folding and stability in the secretory pathway, as well as O-glycosylation at 45 (Thr45) that can modulate cleavage efficiency at nearby sites.

Expression and Tissue Distribution

Sites of Expression

Proopiomelanocortin (POMC) is predominantly expressed in the gland, specifically within corticotroph cells, where it serves as the primary precursor for (ACTH). According to GTEx data, POMC mRNA expression is overexpressed approximately 52.5-fold in the pituitary compared to other tissues, making it the site of highest expression across the . This high level has been confirmed through quantitative real-time PCR (qPCR) analyses, which demonstrate significantly elevated POMC mRNA in pituitary tissue relative to other organs. studies further localize this expression to endocrine cells in the anterior lobe, accounting for the majority of systemic POMC production under basal conditions. Within the , POMC expression is notable in neuroendocrine cells of the arcuate nucleus of the , where it contributes to neuronal signaling related to energy balance. Detection via and qPCR reveals moderate POMC mRNA levels in this region, though substantially lower than in the pituitary—representing a smaller fraction of total central POMC transcripts. Additional hypothalamic sites show trace expression, but the arcuate nucleus remains the principal locus. Cellular localization studies using confirm confinement to neuronal populations in these areas. Peripheral expression of POMC occurs at lower levels in various endocrine and neuroendocrine cells across multiple tissues. In the skin, POMC mRNA is detectable in melanocytes and , as shown by qPCR and , supporting local production. The exhibits POMC gene expression during gestation, primarily in trophoblast cells, identified through PCR-based methods. In the , including the duodenum and colon, POMC mRNA has been observed via and qPCR, localized to enteroendocrine cells. The shows low-level POMC expression in chromaffin cells, quantifiable by qPCR but functionally minor compared to central sites. Overall, these peripheral sites contribute modestly to total POMC under basal conditions, with expression levels orders of magnitude below those in the pituitary.

Developmental and Environmental Regulation of Expression

The expression of the proopiomelanocortin (POMC) gene in the mouse pituitary begins during embryonic development, with onset observed around embryonic day 12.5 (E12.5) in the developing , coinciding with the initiation of corticotroph differentiation following Tpit expression at E11.5. This early expression marks the emergence of POMC-producing cells prior to full maturation of the . POMC transcript levels then increase progressively, reaching a peak in the postnatal period as corticotrophs undergo maturation and enhance their secretory capacity. Several s play critical roles in activating the POMC promoter during development and in mature cells. Tpit (TBX19), a T-box restricted to corticotrophs and melanotrophs, is essential for corticotroph lineage commitment and directly activates POMC transcription by binding to specific response elements in the promoter. NeuroD1, a basic helix-loop-helix , binds directly to motifs in the POMC promoter, forming heterodimers that drive robust activation of transcription in pituitary corticotrophs. (CRH), while not a transcription factor itself, activates the POMC promoter indirectly by stimulating cAMP production and subsequent recruitment of downstream factors like Nur77 to responsive elements. Environmental cues significantly modulate POMC gene transcription in response to physiological demands. Stress hormones such as CRH and arginine vasopressin (AVP) upregulate POMC expression in pituitary corticotrophs primarily through the cAMP/ (PKA) signaling pathway, which enhances promoter activity and ACTH production to mount an adaptive stress response. In contrast, exert by binding to glucocorticoid receptors, which repress POMC transcription via inhibition of cAMP-responsive elements and recruitment of corepressors to the promoter. Epigenetic mechanisms further restrict POMC expression to specific tissues. The POMC promoter contains CpG islands that are heavily methylated in non-pituitary tissues, such as liver and , leading to condensation and transcriptional silencing. This methylation pattern contrasts with the hypomethylated state in pituitary corticotrophs, where it permits active transcription, highlighting tissue-specific epigenetic control.

Biosynthesis and Post-Translational Processing

Cleavage Mechanisms

Proopiomelanocortin (POMC) undergoes endoproteolytic cleavage primarily by prohormone convertases PC1/3 and PC2, which recognize and cleave at paired dibasic residues (Lys-Arg or Arg-Arg) within the precursor protein. These enzymes initiate processing in the trans-Golgi network and continue in immature secretory granules, where the acidic environment (pH 4.5–5.5) and increasing calcium concentrations optimize their activity. Post-cleavage, carboxypeptidase E (CPE) removes the exposed C-terminal basic residues, and peptidylglycine α-amidating monooxygenase (PAM) catalyzes C-terminal amidation of specific peptides, enhancing their stability and bioactivity. Processing is highly tissue-specific, reflecting differential expression of the convertases. In anterior pituitary corticotrophs, PC1/3 predominates and cleaves POMC to generate (ACTH) and β-lipotropin (β-LPH), with minimal further processing due to low PC2 levels. In contrast, melanotrophs of the intermediate pituitary lobe express high levels of both PC1/3 and PC2; PC1/3 performs initial cleavages, while PC2 subsequently processes β-LPH to β-endorphin and γ-lipotropin (γ-LPH), and ACTH to α-melanocyte-stimulating hormone (α-MSH) precursors. This sequential action in secretory granules ensures efficient maturation of peptides for regulated . Species differences influence cleavage efficiency and product profiles. produce higher levels of γ-LPH because their POMC sequence lacks a dibasic cleavage site within this region, preventing further processing into certain γ-MSH variants that occur in humans. Additionally, possess a prominent intermediate pituitary lobe, enabling robust PC2-mediated processing to α-MSH and β-endorphin, whereas humans have a vestigial intermediate lobe, resulting in less extensive melanotroph-like processing.

Derived Peptides and Hormones

Proopiomelanocortin (POMC) is cleaved to generate several bioactive peptides and hormones, primarily through tissue-specific proteolytic processing. The major derivatives include adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), β-endorphin, γ-MSH, β-lipotropin (β-LPH), β-MSH (in humans), and corticotropin-like intermediate peptide (CLIP). ACTH consists of 39 amino acids and lacks disulfide bonds, amidation, or N-terminal acetylation. α-MSH is a 13-amino-acid peptide featuring N-terminal acetylation and C-terminal amidation, which enhance its stability and activity, but no disulfide bonds. β-Endorphin comprises 31 amino acids, with potential N-terminal acetylation in certain tissues but no disulfide bonds or consistent amidation. γ-MSH (specifically γ2-MSH) is a 12-amino-acid peptide without disulfide bonds, amidation, or acetylation. β-LPH is an 91-amino-acid precursor peptide that itself undergoes further cleavage, lacking these modifications. β-MSH is an 18-amino-acid peptide derived from γ-LPH in humans, with N-terminal acetylation and C-terminal amidation. CLIP is a 22-amino-acid peptide derived from the C-terminus of ACTH, lacking modifications. The joining peptide region yields an amidated peptide that forms a homodimer linked by a cysteine bridge in humans.
PeptideAmino AcidsKey Structural Features
ACTH39None (no disulfides, amidation, or )
α-MSH13N-terminal , C-terminal amidation
β-Endorphin31Possible N-terminal
γ-MSH (γ2)12None
β-LPH91None
β-MSH18N-terminal , C-terminal amidation
CLIP22None
One POMC precursor molecule stoichiometrically produces one ACTH and one β-LPH in the , while intermediate lobe or hypothalamic processing yields one α-MSH, one CLIP, and one instead of intact ACTH and β-LPH, with variations in γ-MSH and β-MSH output depending on tissue-specific enzymes. The core sequences of these derived peptides exhibit high evolutionary conservation, with over 90% identity in key regions such as the melanocortin core (His-Phe-Arg-Trp) of ACTH and MSH peptides across vertebrates, reflecting their ancient origins over 500 million years ago. For instance, α-MSH shows approximately 85% sequence identity even between mammals and certain invertebrates, while and ACTH maintain near-complete conservation among mammals.

Physiological Roles

Involvement in the Hypothalamic-Pituitary-Adrenal Axis

Proopiomelanocortin (POMC) plays a central role in the hypothalamic-pituitary-adrenal (HPA) axis by serving as the precursor to (ACTH), which mediates the stress response. (CRH), secreted by the paraventricular nucleus of the in response to stress, binds to CRH receptors on anterior pituitary corticotroph cells, stimulating the transcription of the POMC and subsequent processing of POMC into ACTH. ACTH is then released into the systemic circulation, where it travels to the to bind melanocortin-2 receptors, promoting the synthesis and secretion of glucocorticoids, primarily in humans. This cascade enables a rapid neuroendocrine response to maintain during stress. Negative feedback mechanisms tightly regulate POMC expression and ACTH release to prevent overactivation of the HPA axis. Circulating glucocorticoids, such as , exert inhibitory effects by binding to receptors (GR) in the pituitary, which translocate to the nucleus and interact with negative glucocorticoid response elements (nGREs) in the POMC promoter, suppressing POMC transcription. This direct genomic repression, along with nongenomic actions that reduce CRH receptor sensitivity, ensures that elevated levels dampen further POMC-derived ACTH production. The HPA axis response involving POMC-derived ACTH differs between acute and scenarios. In acute stress, CRH rapidly induces a surge in POMC mRNA and ACTH secretion, leading to a quick rise in within minutes to support immediate adaptive responses. During , prolonged CRH stimulation sustains elevated POMC expression and ACTH release, but feedback mechanisms may lead to partial desensitization, resulting in a blunted or dysregulated output over time. ACTH's short plasma half-life of approximately 10 minutes facilitates precise pulsatile signaling, contributing to the diurnal rhythm of secretion, with peak levels in the early morning driven by amplified morning ACTH pulses.

Regulation of Pigmentation, Appetite, and Energy Balance

Proopiomelanocortin (POMC)-derived peptides play a central role in regulating skin pigmentation through the action of α-melanocyte-stimulating hormone (α-MSH), which binds to the melanocortin 1 receptor (MC1R) on melanocytes. This binding activates Gs-coupled signaling, elevating intracellular cyclic AMP (cAMP) levels and stimulating protein kinase A (PKA), which in turn promotes the synthesis of eumelanin—the dark pigment responsible for skin and hair darkening—via upregulation of tyrosinase and related enzymes. α-MSH also activates the MAPK/ERK pathway, which synergizes with cAMP signaling to enhance eumelanin production and inhibit pheomelanin synthesis. These mechanisms collectively increase melanin deposition, protecting against ultraviolet radiation damage. In the , POMC neurons in the arcuate nucleus of the suppress appetite by releasing α-MSH and β-endorphin, which act on melanocortin-4 receptors () expressed on downstream second-order neurons. Activation of inhibits orexigenic neurons co-expressing (NPY) and agouti-related peptide (AgRP), thereby reducing food intake and promoting signals that project to regions like the paraventricular nucleus. β-Endorphin contributes to this process by modulating opioid receptors, though its effects can sometimes oppose strict suppression through reward pathways. Disruptions in this circuit, such as mutations, lead to hyperphagia and , underscoring the anorexigenic dominance of POMC signaling. POMC-derived peptides also maintain energy homeostasis by integrating satiety with metabolic adjustments, where overall activation promotes thermogenesis and energy expenditure. α-MSH signaling via MC4R enhances brown adipose tissue activity and lipolysis, increasing heat production to counter weight gain. Meanwhile, β-endorphin influences reward-driven eating behaviors, potentially amplifying hedonic consumption of palatable foods, which can complicate net energy balance in obesogenic environments. This dual modulation ensures adaptive responses to nutritional states, with POMC neuron stimulation favoring negative energy balance through reduced intake and heightened expenditure. Leptin, an adiposity signal from , stimulates POMC expression and neuronal activity in the arcuate nucleus via leptin receptors, enhancing α-MSH release to reinforce suppression and expenditure. In , hypothalamic leptin resistance diminishes this stimulation, reducing POMC-derived output and contributing to hyperphagia and metabolic dysfunction. This leptin-POMC axis thus links peripheral stores to central control, with impaired signaling promoting through lowered and thermogenic drive. Central actions predominate for and , distinct from peripheral roles in pigmentation.

Other Systemic Functions

Beta-endorphin, a key derivative of proopiomelanocortin (POMC), exerts effects by binding to mu-opioid receptors in the central and peripheral nervous systems. In the , it acts presynaptically to inhibit the release of from primary afferent neurons, thereby reducing nociceptive signal transmission to the . Similarly, in the , beta-endorphin modulates through mu-opioid receptors in regions such as the matter and rostral ventral medulla, inhibiting and enhancing descending inhibitory pathways. POMC-derived peptides like (ACTH) and alpha-melanocyte-stimulating hormone (α-MSH) play significant roles in immune modulation by suppressing inflammatory responses in leukocytes. ACTH binds to 3 receptors (MC3R) on macrophages, inhibiting their activation, , and release of proinflammatory cytokines such as interleukin-1β (IL-1β). α-MSH, acting via MC3R and 5 receptors (MC5R) on immune cells including neutrophils and lymphocytes, reduces the production of tumor necrosis factor-α (TNF-α) and IL-6 while promoting IL-10 secretion, primarily through inhibition of signaling. Melanocortin peptides derived from POMC influence cardiovascular function, particularly regulation, through central (MC4R) activation. Intracerebroventricular administration of α-MSH elevates and by enhancing outflow from the and . This effect is mediated by MC4R in key autonomic centers, where agonist stimulation increases neuronal activity in sympathoexcitatory pathways, contributing to in experimental models. In reproductive physiology, POMC expression in the generates local ACTH that supports fetal development and growth. Placental ACTH, processed from POMC, stimulates (LIF) secretion from fetal nucleated red blood cells, which in turn promotes and maturation of the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, it facilitates histogenesis and testicular development via activation of MC2R and MC5R in fetal tissues, ensuring proper and endocrine function during .

External Regulation

Photoperiod and Circadian Influences

Photoperiod, the duration of daily light exposure, plays a critical role in regulating proopiomelanocortin (POMC) expression and processing in seasonal mammals, primarily through the pineal gland's secretion of melatonin, which encodes environmental light cues. In Syrian hamsters (Mesocricetus auratus), exposure to long photoperiods (e.g., 14 hours light:10 hours dark) results in fewer POMC-expressing cells in the hypothalamic arcuate nucleus compared to short photoperiods (e.g., 5 hours light:19 hours dark), indicating suppression of POMC neuronal recruitment under extended daylight conditions. This effect is mediated by reduced nocturnal melatonin duration in long days, as pinealectomy abolishes the photoperiodic influence on both the density of POMC mRNA-positive cells and the expression level per cell. Similarly, in Soay sheep (Ovis aries), transition from long to short days stimulates increased secretion of POMC-derived α-melanocyte-stimulating hormone (α-MSH) and β-endorphin from the pituitary intermediate lobe, supporting seasonal adaptations in energy balance and reproduction. These changes highlight how melatonin signaling transduces photoperiodic information to modulate hypothalamic and pituitary POMC systems, with long days generally suppressing expression to align with periods of reproductive quiescence or energy storage. Circadian rhythms also impose daily oscillations on POMC expression, particularly in the , though POMC mRNA levels do not exhibit a significant 24-hour rhythm in under standard 12:12 light-dark cycles; instead, ACTH release shows coordinated daily patterns. In the hypothalamic arcuate nucleus, circadian clock components influence POMC neuronal activity, though feeding-entrained cues can phase-shift these patterns, underscoring the interplay between central clocks and peripheral metabolic signals. At the molecular level, acts via MT1 and MT2 receptors to inhibit (CRH) release from the hypothalamic paraventricular nucleus, thereby reducing downstream stimulation of pituitary POMC transcription and processing into ACTH. This inhibitory pathway predominates under short photoperiods, where prolonged secretion paradoxically enhances selective POMC-derived peptides like α-MSH in certain contexts, such as promoting fur molting and pigmentation changes for seasonal . In short-day conditions, elevated α-MSH levels from POMC processing facilitate cycle transitions, including anagen induction for winter development in mammals like sheep and hamsters, contrasting with the suppressive effects on the full HPA axis activation. Experimental evidence confirms the pineal gland's essential role, as pinealectomy in Syrian hamsters eliminates photoperiod-dependent variations in hypothalamic POMC mRNA abundance and cell number, regardless of gonadal status or replacement, while exogenous administration restores these responses. These findings demonstrate that intact signaling is indispensable for photoperiodic tuning of POMC, with disruptions leading to desynchronized seasonal phenotypes in and reproductive timing.

Hormonal and Neural Controls

The regulation of proopiomelanocortin (POMC) expression and activity is profoundly influenced by systemic hormonal signals, particularly in the arcuate nucleus of the and the . Insulin and , key metabolic hormones, upregulate POMC gene expression in arcuate POMC neurons primarily through activation of the signal transducer and activator of transcription 3 () pathway, which promotes anorexigenic effects and . This STAT3-mediated mechanism integrates nutrient sensing with POMC-derived peptide production, such as α-melanocyte-stimulating hormone (α-MSH), to suppress during states of surplus. Additionally, sex steroids like enhance POMC expression and ACTH content in pituitary corticotrophs, contributing to sex-specific modulation of the stress response and reproductive axis. Neural inputs further fine-tune POMC function through limbic-hypothalamic pathways. Excitatory projections from the to corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the amplify stress signals that stimulate pituitary POMC transcription and ACTH release, whereas hippocampal inputs often exert inhibitory effects on PVN CRH activity, providing contextual regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Sympathetic innervation of the also modulates local POMC expression, influencing the processing and release of POMC-derived peptides in response to autonomic arousal. Feedback mechanisms involving inflammatory signals integrate immune challenges with POMC activation. During , cytokines such as interleukin-1 (IL-1) bind to receptors on hypothalamic and pituitary POMC neurons, boosting POMC mRNA expression and enhancing the stress response to facilitate release. Pharmacological modulators, including endogenous opioids derived from POMC itself, exert inhibitory control via μ-opioid autoreceptors on POMC neurons, dampening further release and preventing overstimulation in feedback loops.

Clinical and Pathological Aspects

Associated Disorders and Mutations

Mutations in the proopiomelanocortin (POMC) gene lead to a rare monogenic disorder characterized by early-onset severe obesity, pale skin with red hair due to lack of melanocyte-stimulating hormone (MSH), and adrenal insufficiency resulting from deficient adrenocorticotropic hormone (ACTH) production. This condition arises from biallelic loss-of-function mutations that impair POMC transcription or processing, preventing the generation of bioactive peptides essential for energy homeostasis, pigmentation, and glucocorticoid regulation. A specific example is the R236G missense mutation, which disrupts a dibasic cleavage site in the POMC prohormone, resulting in a fusion protein that fails to activate melanocortin receptors properly and exacerbates susceptibility to obesity and adrenal dysfunction. In endocrine contexts, dysregulation of POMC expression contributes to disorders of cortisol homeostasis. Overexpression of POMC in pituitary corticotroph adenomas drives excessive ACTH secretion, leading to Cushing's disease, a condition marked by hypercortisolism, central obesity, and metabolic disturbances. Conversely, POMC deficiency manifests as primary adrenal insufficiency akin to Addison's disease, where hypocortisolism stems from inadequate ACTH stimulation of the adrenal glands, often presenting with fatigue, hypotension, and life-threatening salt-wasting crises in infancy. POMC-related obesity syndromes primarily result from impaired signaling in the . Biallelic POMC abolish alpha-MSH production, reducing activation of the () and causing hyperphagia, rapid weight gain, and severe from early childhood. Heterozygous POMC variants, representing , do not typically cause monogenic obesity but are associated with modestly increased and subtle disruptions in regulation through partial pathway impairment. Recent investigations have linked POMC dysfunction to neuropsychiatric conditions, particularly through deficits in beta-endorphin, a POMC-derived with anxiolytic properties. Post-2020 studies indicate that genetic variations in POMC, such as the rs2071345 polymorphism, interact with environmental factors to heighten anxiety symptoms, potentially exacerbating disorders like in susceptible individuals. This suggests beta-endorphin deficiency may contribute to heightened stress responses and mood dysregulation in POMC-related pathologies.

Therapeutic Targeting and Drug Development

Therapeutic targeting of proopiomelanocortin (POMC)-derived peptides has advanced through the development of agonists, analogs, and antagonists that modulate , adrenocorticotropic, and pathways. , a cyclic octapeptide analog of α-melanocyte-stimulating hormone (α-MSH), acts as a agonist to treat associated with POMC deficiency. This drug was approved by the U.S. (FDA) in November 2020 for chronic weight management in patients aged 2 years and older with due to biallelic POMC mutations, with the indication expanded to include children aged 2 to 5 years in December 2024, as confirmed by phase 3 clinical trials demonstrating significant reductions in body weight and hunger scores. In these trials, led to a mean of 25% in adults and 10-15% in adolescents with POMC deficiency over one year, highlighting its role in restoring signaling disrupted by POMC defects. Recent phase 3 pediatric data from 2024 showed a mean reduction in BMI Z-score of 3.04, supporting its efficacy in younger patients. As of 2025, a phase 2 trial for Prader-Willi syndrome was initiated in early 2025 to further explore 's potential in related hyperphagia disorders. Analogs of (ACTH), a key POMC cleavage product, are utilized in diagnostic and therapeutic contexts for adrenal disorders. Tetracosactide, a synthetic 24-amino-acid analog of human ACTH (corresponding to residues 1-24), is employed in the short Synacthen test to assess adrenocortical function and diagnose primary or secondary . Administered intramuscularly or intravenously at a dose of 250 μg, tetracosactide stimulates release, with post-stimulation levels above 18-20 μg/dL indicating normal adrenal reserve. This analog mimics the biological activity of endogenous ACTH without the risks of full-length pituitary extracts, making it a standard tool for evaluating hypothalamic-pituitary-adrenal axis integrity. Opioid antagonists target β-endorphin, another POMC-derived , to mitigate reward pathways in . , a competitive μ- , blocks the euphoric and reinforcing effects of endogenous like β-endorphin, reducing cravings in alcohol use disorder and opioid dependence. FDA-approved for these indications since 1994, at oral doses of 50 mg daily or extended-release intramuscular injections of 380 mg monthly decreases rates by 20-50% in clinical trials, partly by antagonizing β-endorphin-mediated release in the . Studies in former opioid addicts have shown that chronic administration elevates serum β-endorphin levels as a compensatory response, supporting its mechanism in desensitizing opioid reward circuits. Emerging strategies include to address POMC mutations and melanocortin mimetics for applications. Preclinical research explores (AAV)-mediated delivery to restore POMC expression in hypothalamic neurons, aiming to correct energy imbalance in deficiency states, though no clinical trials have advanced to human testing yet. For autoimmune diseases, synthetic α-MSH mimetics targeting exhibit potent effects by suppressing pro-inflammatory production (e.g., TNF-α, IL-6) in models of and . These compounds, such as AP214 and BMS-470539, have progressed to early-phase trials, demonstrating reduced joint inflammation and immune without broad .

Interactions and Comparative Biology

Protein-Protein Interactions

Proopiomelanocortin (POMC) and its processed derivatives engage in specific protein-protein interactions critical for their maturation, trafficking, and signaling functions. (ACTH), a key POMC-derived , binds with high affinity to the melanocortin 2 receptor (MC2R), exhibiting a (Kd) of approximately 0.13 nM in adrenal cell models. ACTH also interacts with the melanocortin 5 receptor (MC5R), though with lower affinity compared to MC2R, typically in the nanomolar range, supporting its role in functions. Similarly, α-melanocyte-stimulating hormone (α-MSH), another POMC product, binds to MC1R with a Ki of about 0.41 nM, facilitating pigmentation control in melanocytes. α-MSH further associates with MC3R (Kd ≈ 3.8 nM) and (Kd ≈ 1.6 nM), influencing through receptors. The proteolytic processing of POMC relies on interactions within the proprotein convertase family. In secretory granules, prohormone convertase 1/3 (PC1/3) and PC2 form a complex that sequentially cleaves POMC at dibasic sites to generate ACTH, α-MSH, and β-endorphin, with PC1/3 initiating the process in the anterior pituitary and PC2 completing it in the intermediate lobe. The chaperone protein 7B2 binds to proPC2, facilitating its activation and enhancing the efficiency of POMC cleavage in neuroendocrine cells. This interaction prevents premature activity of PC2 and ensures proper folding within the granule environment. Downstream signaling involves stable complexes between POMC derivatives and G-protein-coupled receptors. Upon binding to MC4R, α-MSH induces conformational changes that couple the receptor to the stimulatory G protein (Gs), leading to adenylate cyclase activation and elevated cyclic AMP (cAMP) levels. Recent studies have also identified coupling to G12/13 proteins in POMC neurons, which contributes to glucose homeostasis regulation in mice. Cryo-electron microscopy structures, including those from 2021 and more recent 2024 analyses, confirm these Gs-mediated interactions and reveal ligand-specific details, highlighting key residues in transmembrane helix 3 of MC4R that stabilize ligand binding and signal propagation. Proteomic approaches have identified additional interactions supporting POMC trafficking. Co-immunoprecipitation studies reveal that the N-terminal region of POMC binds to carboxypeptidase E (CPE) in the trans-Golgi network, acting as a sorting receptor to direct POMC into the regulated secretory pathway. Yeast two-hybrid screens and co-IP assays further demonstrate associations with granin family proteins, such as secretogranin II, which aid in granule formation and POMC packaging, though direct links to sorting nexins remain less characterized in mammalian systems.

Variations in Non-Human Species

In , proopiomelanocortin (POMC) undergoes distinct posttranslational processing compared to humans, with no production of β-melanocyte-stimulating hormone (β-MSH) due to alterations in cleavage sites, leading to α-MSH serving as the primary in hypothalamic neurons. Additionally, the N-terminal region of POMC in yields multiple γ-MSH variants, including γ1-MSH, γ2-MSH, and γ3-MSH, which exhibit species-specific potencies at and contribute to natriuretic functions. POMC knockout models in mice demonstrate adult-onset characterized by hyperphagia, reduced energy expenditure, defective adrenal development, and altered pigmentation, underscoring the conserved role of POMC-derived peptides in across mammals. In dogs, a 14-base pair deletion in the POMC gene disrupts the coding sequences for β-MSH and , resulting in a premature and loss of these peptides, which is strongly associated with increased body weight, heightened food motivation, and risk in Labrador retrievers. This variant has an of approximately 12-25% in the breed, leading to lower resting metabolic rates and elevated hunger signals without affecting adrenal function. The mutation highlights POMC's clinical relevance in canine , paralleling monogenic forms in other species but with breed-specific prevalence. Fish and amphibians exhibit greater structural diversity in POMC, often with duplicated genes such as POMCa and POMCb in teleosts, where POMCb lacks the N-terminal region and retains only α-MSH and β-endorphin sequences, reflecting lower evolutionary conservation in the compared to the more preserved central and C-terminal domains. This expanded MSH family, including α-MSH, β-MSH, and additional variants like δ-MSH in some species, plays a key role in rapid through pigment dispersion in chromatophores and melanophores, enabling background for . In amphibians, the POMC precursor maintains three core domains but shows functional specialization for skin darkening during stress or environmental changes, differing from the more integrated metabolic roles in tetrapods. In avian species, POMC processing and expression contribute to stress responses via the hypothalamo-pituitary-adrenal (HPA) axis, but differ from mammals in regulatory mechanisms, with (CRH) and arginine vasotocin synergistically stimulating POMC-derived (ACTH) release rather than vasopressin dominance. Birds lack certain mammalian HPA components, such as a direct analog to pro-opiomelanocortin N-terminal peptides in adrenal regulation, leading to distinct feedback and stress-induced behaviors, as seen in upregulated POMC transcription during acute stressors but dampened responses in domesticated lines. This comparative emphasizes POMC's adaptability in avian and immune modulation under stress, without the full mammalian HPA integration.

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