Within our bodies, a molecule known as pro-opiomelanocortin (POMC) operates as a master precursor. It is a large, inactive protein whose significance comes from its potential to be divided into several smaller, active peptide hormones, each with a distinct job. This process of creating multiple functional molecules from a single precursor is an efficient biological strategy, highlighting its central role in maintaining the body’s internal balance.
The Creation and Processing of POMC
The journey of pro-opiomelanocortin begins with its synthesis in specialized cells. The primary production sites are the corticotroph cells of the anterior pituitary gland and a cluster of neurons in the arcuate nucleus of the hypothalamus. In these locations, the POMC gene provides the blueprint for assembling a long polypeptide chain of 241 amino acids, which then becomes the POMC prohormone.
Once synthesized, POMC undergoes a process called post-translational modification, specifically proteolytic cleavage. This happens inside cellular compartments where specialized enzymes known as prohormone convertases (PCs) act like molecular scissors. These enzymes cut the long POMC chain at specific sites, which are marked by pairs of basic amino acids, liberating the smaller, active hormones.
The outcome of this cutting process is highly dependent on the tissue where it occurs. The set of enzymes present in the pituitary’s corticotroph cells is different from that in the hypothalamic neurons. For instance, prohormone convertase 1 (PC1/3) is the main enzyme in the anterior pituitary, while hypothalamic neurons utilize both PC1/3 and PC2. This tissue-specific expression allows different sets of hormones to be produced from the same POMC precursor.
Key Hormones Derived from POMC
The cleavage of POMC gives rise to several important hormones, with the specific peptides produced depending on the processing tissue.
Adrenocorticotropic hormone (ACTH)
In the anterior pituitary gland, the primary product of POMC cleavage is adrenocorticotropic hormone (ACTH). ACTH is a central player in the body’s response to stress. When released into the bloodstream, it travels to the adrenal glands, located on top of the kidneys. There, it stimulates the adrenal cortex to produce and release glucocorticoid hormones, mainly cortisol, which helps the body cope with stressful situations.
Melanocyte-stimulating hormones (MSHs)
Further processing of the ACTH molecule, particularly in hypothalamic neurons and the skin, yields alpha-melanocyte-stimulating hormone (α-MSH). In the skin, α-MSH stimulates pigment-producing cells called melanocytes to produce melanin, which gives skin and hair their color and provides protection from ultraviolet radiation. In the brain, α-MSH acts as an appetite suppressant by signaling to reduce food intake and increase energy expenditure.
β-Endorphin
Another product derived from POMC, primarily in the brain, is β-endorphin. This peptide is one of the body’s endogenous opioids, functioning as a natural pain reliever. By binding to opioid receptors in the brain, β-endorphin blocks pain signals and is also associated with feelings of pleasure, famously contributing to the phenomenon known as “runner’s high.”
Regulation of the POMC System
The production and release of POMC and its derivatives are tightly controlled. The primary activator is corticotropin-releasing hormone (CRH), released from the hypothalamus in response to stress. CRH travels to the anterior pituitary, stimulating corticotroph cells to secrete POMC-derived peptides like ACTH. This forms the initial leg of the hypothalamic-pituitary-adrenal (HPA) axis, the body’s central stress response system.
The HPA axis features a negative feedback loop that prevents an excessive stress response. As ACTH stimulates the adrenal glands to produce cortisol, rising cortisol levels circulate back to the brain. There, cortisol inhibits the secretion of ACTH and CRH from the pituitary gland and hypothalamus, respectively.
Hormonal signals also influence POMC neurons involved in appetite control. The hormone leptin, produced by fat cells, regulates energy balance. When fat stores are sufficient, leptin stimulates POMC neurons, increasing the release of the appetite-suppressing hormone α-MSH and signaling satiety.
Health Implications of POMC Dysfunction
Disruptions in the pro-opiomelanocortin system, whether through genetic mutations or tumors, can lead to significant health problems. The consequences depend on whether the system is underactive or overactive, reflecting the functions of the hormones that are either missing or in excess.
A primary example of underactivity is POMC deficiency, a rare genetic disorder caused by mutations in the POMC gene. This leads to a distinct set of symptoms: severe, early-onset obesity due to the absence of α-MSH; adrenal insufficiency because of the lack of ACTH; and often, pale skin and red hair from insufficient α-MSH. Without treatment for the adrenal insufficiency, this condition can be life-threatening.
Conversely, overproduction of POMC-derived peptides can also cause disease. The most common scenario involves a non-cancerous tumor of the pituitary gland’s corticotroph cells, which leads to Cushing’s disease. The tumor autonomously secretes excessive amounts of ACTH, leading to chronic overstimulation of the adrenal glands and high cortisol levels. Symptoms include central weight gain, high blood pressure, muscle weakness, mood changes, and sometimes hyperpigmentation of the skin.