Proopiomelanocortin

Gene

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

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:

• Corticotropic cells of the anterior pituitary gland
• Melanotropic cells of the intermediate lobe of the pituitary gland
• Neurons of the arcuate nucleus (infundibular nucleus) in the hypothalamus
• Smaller populations of neurons in the dorsomedial hypothalamus and brainstem
• Melanocytes in the skin.

Function

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:

• α-MSH produced by neurons in the ventromedial nucleus has important roles in the regulation of appetite (POMC neuron stimulation results in satiety.) and sexual behavior, while α-MSH secreted from the intermediate lobe of the pituitary regulates the movement of melanin produced from melanocytes in skin.
• ACTH is a peptide hormone that regulates the secretion of mainly glucocorticoids from the cells of the zona fasciculata of the adrenal cortex. ACTH can also regulate secretion of gonadocorticoids from the cells of the zona reticularis since they also express ACTH receptors.
• β-Endorphin and [Met]enkephalin are endogenous opioid peptides with widespread actions in the brain.

Post-translational modifications

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).

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.

Derivatives

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 ε-Melanocyte-Stimulating Hormone (ε-MSH), present in some teleost fish 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, β-Endorphin is not generally believed to be a precursor of [Met]enkephalin. 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

The levels of proopiomelanocortin (pomc) are regulated indirectly in some animals by the photoperiod. It is referred to 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.

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.

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

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

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.

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.

Increased circulating levels of POMC have also been observed in patients with sepsis. 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.

Drug target

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

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.

Dogs

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

Interactions

Proopiomelanocortin has been shown to interact with melanocortin 4 receptor. 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.

References

References

1. "pro-opiomelanocortin preproprotein [Homo sapiens] - Protein - NCBI".
2. (1995). "Opioid precursor gene expression in the human hypothalamus". Journal of Comparative Neurology.
3. (May 2001). "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus". Nature.
4. (2007). "Proopiomelanocortin (POMC), the ACTH/melanocortin precursor, is secreted by human epidermal keratinocytes and melanocytes and stimulates melanogenesis". FASEB Journal.
5. (December 2012). "Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis". EMBO Reports.
6. (August 2003). "Presence of the delta-MSH sequence in a proopiomelanocortin cDNA cloned from the pituitary of the galeoid shark, Heterodontus portusjacksoni". General and Comparative Endocrinology.
7. (January 2014). "Complex structural and regulatory evolution of the pro-opiomelanocortin gene family". General and Comparative Endocrinology.
8. (2022). "StatPearls". StatPearls Publishing.
9. (August 2007). "Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction". Endocrinology.
10. (June 2019). "Genome sequencing and transcriptome analyses of the Siberian hamster hypothalamus identify mechanisms for seasonal energy balance". Proceedings of the National Academy of Sciences of the United States of America.
11. (2012). "An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity". PLOS Genetics.
12. "POMC proopiomelanocortin". Entrez Gene.
13. (2017). "Medical Physiology". Elsevier.
14. (2017). "Study of obesity associated proopiomelanocortin gene polymorphism: Relation to metabolic profile and eating habits in a sample of obese Egyptian children and adolescents.". Egyptian Journal of Medical Human Genetics.
15. (February 2021). "The role of pro-opiomelanocortin in the ACTH-cortisol dissociation of sepsis". Critical Care.
16. (January 2022). "Impact of Hydrocortisone and of CRH Infusion on the Hypothalamus-Pituitary-Adrenocortical Axis of Septic Male Mice". Endocrinology.
17. (June 2014). "Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss". Pharmacological Research.
18. (July 2016). "Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist". The New England Journal of Medicine.
19. (May 2016). "A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs". Cell Metabolism.
20. (December 2000). "Molecular determinants of ligand binding to the human melanocortin-4 receptor". Biochemistry.
21. (March 1997). "Effects of recombinant agouti-signaling protein on melanocortin action". Molecular Endocrinology.