Creative Touch Permanent Makeup and Aesthetics

Pro-opiomelanocortin (POMC) is a 267- amino acid precursor protein encoded by a single gene, whose biological significance lies entirely in what is done to it after synthesis. Tissue-specific processing by two prohormone convertases – PC1/3 and PC2 – produces entirely different peptide repertoires in different tissues: the pituitary predominantly yields ACTH; the hypothalamus and skin yield α-MSH, β-MSH, and β-endorphin through more extensive PC2-mediated cleavage. In the hypothalamic arcuate nucleus, POMC-expressing neurons constitute the principal anorexigenic arm of the melanocortin appetite circuit, releasing α-MSH to activate MC4R and suppress food intake and promote energy expenditure – the direct functional counterpart of AgRP/NPY orexigenic neurons acting on the same receptors in the opposing direction. Loss-of-function POMC mutations in humans produce severe early-onset obesity with hyperphagia, glucocorticoid deficiency, and – because α-MSH/MC1R-driven eumelanin production is impaired – characteristically pale skin and red hair, the triad that established the melanocortin pathway as causal in human body weight regulation. In skin, POMC is expressed locally and processed in situ to produce the same cleavage products – enabling a complete local HPA-axis homologue operating independently of the central axis.

POMC is the paradigm case of a precursor protein whose identity is meaningless without specifying its processing context. The gene produces one transcript, translated into one protein – but from that single protein, the tissue can extract an appetite suppressant, a stress hormone, a photoprotective signal, or an analgesic, depending solely on which convertase enzymes are present and active. This functional versatility is not a design coincidence: the melanocortin system uses shared receptor infrastructure ( MC1R–MC5R), shared ligand precursor (POMC), and a shared antagonist (AgRP/ASIP) across the brain, skin, adrenal gland, and immune system simultaneously – a unified hormonal architecture with tissue-specific outputs.

One Gene, Many Signals: The Cleavage Architecture

POMC is cleaved in a defined sequence by two prohormone convertases whose relative expression levels determine which peptides a given tissue produces. ^[3]

PC1/3 is the first-stage convertase, expressed in anterior pituitary corticotrophs and in hypothalamic neurons. It cleaves POMC at dibasic amino acid sites to produce ACTH (39 amino acids), β-lipotropin (β-LPH), and an N-terminal fragment. In anterior pituitary corticotrophs – where PC2 expression is low – this is where processing largely stops: ACTH and β-LPH are the dominant outputs. ACTH then acts on adrenal MC2R to drive cortisol synthesis, forming the conventional HPA axis.

PC2 is the second-stage convertase, expressed in hypothalamic neurons, the intermediate pituitary, and in skin. Its presence allows further cleavage of the PC1/3 products: ACTH is cleaved to α-MSH (ACTH 1–13, with N-terminal acetylation and C-terminal amidation) and CLIP; β-LPH is cleaved to β-endorphin and β-MSH; the N-terminal fragment is processed to γ-MSH. ^[3] In PC2-expressing tissues, the product profile therefore shifts away from ACTH toward the melanotropins and opioids – the same gene producing a fundamentally different hormonal output.

The tissue-specificity of this processing has a direct clinical consequence. In hypothalamic POMC neurons, PC2 activity means α-MSH is the primary bioactive product and the principal appetite-suppressing signal. In skin keratinocytes and melanocytes, PC2 activity produces the same α-MSH locally in response to UV – driving pigmentation through MC1R without requiring pituitary ACTH as an intermediary. ^[3] A 2025 study further identified that once secreted, extracellular POMC in skin undergoes additional processing by skin-associated proteases to generate shorter, bioactive α-MSH fragments including α-MSH(1–8), suggesting the cutaneous processing of POMC continues beyond the intracellular step. ^[8]

Central POMC: The Anorexigenic Neuron

POMC-expressing neurons in the ventromedial arcuate nucleus constitute one of the two fundamental populations regulating energy homeostasis. Their defining function – confirmed directly by optogenetic activation studies producing acute food intake suppression, and by POMC knockout mouse models producing hyperphagia and obesity – is to signal satiety and promote energy expenditure through α-MSH release at downstream MC4R-expressing neurons, particularly in the paraventricular nucleus of the hypothalamus. ^[5]

Multiple hormonal inputs converge on POMC neurons as upstream activators:

• Leptin directly depolarises POMC neurons via LepRb, increasing their firing rate and α-MSH release – making POMC neurons a primary effector of leptin’s anorexigenic action. Leptin simultaneously hyperpolarises adjacent AgRP/ NPY neurons, creating coordinated reciprocal suppression of hunger drive.
• Insulin activates POMC neurons via PI3K signalling, contributing to post-meal satiety.
• Serotonin activates POMC neurons through 5-HT2C receptors expressed on their surface – a mechanism exploited by appetite-modulating drugs, and consistent with the observed reduced food intake following serotonergic activation of this pathway. ^[6]
• GLP-1 acts on GLP-1 receptors expressed by a subset of POMC neurons, contributing to the appetite suppression produced by GLP-1 receptor agonist medications alongside their AgRP-suppressing action.

POMC neurons are functionally heterogeneous. ^[6] Not all arcuate POMC neurons respond equivalently to leptin, serotonin, or other inputs – subpopulations respond preferentially to one hormone class over another, and their downstream projections differ. This heterogeneity partially explains why POMC neuron activation’s effects on food intake and on energy expenditure are dissociable: some subpopulations drive satiety signalling; others modulate sympathetic outflow to peripheral organs, including hepatic glucose regulation via the sympathetic liver innervation. ^[7] A single hormonal label – “POMC neuron” – contains multiple distinct functional entities that research is still characterising.

The Reciprocal Arc: POMC and AgRP as Coordinated Counterparts

Appetite regulation in the arcuate nucleus is not simply POMC active or inactive – it is the simultaneous and reciprocal modulation of POMC and AgRP neuron activity that governs the feeding state. In satiety, POMC neurons are activated and AgRP/NPY neurons are inhibited; in hunger, AgRP/NPY neurons are activated and POMC neurons are inhibited. Both transitions happen together, not sequentially.

De Solis et al. (2024) directly tested the contribution of each population’s activity and their interaction, using simultaneous chemogenetic DREADD expression in both neuron populations in the same animal. ^[2] Key findings: food intake was regulated by the additive effect of AgRP activation and POMC inhibition – meaning both changes contribute independently and their combination produces greater hyperphagia than either alone. However, insulin sensitivity and hepatic gluconeogenesis were differentially regulated by isolated versus simultaneous manipulation – pointing to distinct metabolic roles that are not simply additive. The two populations converge in their feeding effects at Npy1R-expressing neurons in the paraventricular nucleus, where activated AgRP signals and suppressed POMC signals cooperate to promote food consumption.

The clinical implication of the additive model is that the hunger state experienced during the four-hour post-meal glucose nadir is driven by both components simultaneously: AgRP neurons activated by declining glucose and blocked fat oxidation, and POMC neurons correspondingly inhibited as leptin falls with prolonged inter-meal fasting and insulin-mediated suppression of POMC activation wanes. The craving is not AgRP alone or POMC failure alone – it is the coordinated transition of the entire melanocortin circuit toward its hunger configuration.

The Cutaneous HPA Axis and POMC

The skin expresses a complete functional homologue of the hypothalamic-pituitary-adrenal axis, operating as a localised stress-response system independent of – though capable of communicating with – the central HPA axis. This cutaneous HPA axis includes local expression of CRH, POMC, and the downstream receptors for their cleavage products, enabling keratinocytes and melanocytes to generate ACTH, α-MSH, and β-endorphin in situ in response to UV irradiation, physical injury, or stress signals. ^[4] The biological function of this local system is integrative – simultaneously coordinating photoprotective pigmentation (α-MSH→MC1R→ MITF→eumelanin), local cortisol synthesis (ACTH→MC2R), anti-inflammatory signalling (α-MSH suppressing NF-κB), and pain and itch modulation (β-endorphin→opioid receptors) within the same tissue under the same stimulus.

The UV wavelength-dependence of cutaneous POMC activation is clinically relevant. UVB and UVC are the primary activating stimuli, operating through the UV→p53→POMC pathway in keratinocytes; UVA activates overlapping but partially distinct mechanisms. ^[4] This wavelength specificity means that broad-spectrum UV exposure from natural sunlight engages the full cutaneous POMC system in a way that filtered or narrowband light sources may not replicate. This local POMC-to-α-MSH processing in skin is the mechanism connecting dietary and metabolic state to photoprotective capacity: because MC1R activation by α-MSH drives the eumelanin-phaeomelanin switch, anything that impairs POMC processing or MC1R expression in skin (including the ASIP/MC1R balance described in AgRP) modifies the skin’s ability to deploy the photoprotective response that UV-driven POMC synthesis is designed to deliver.