Overview of POMC and downstream effects and regulation
Read this to understand one of the master peptides in the body
Proopiomelanocortin (POMC) is a precursor polypeptide (241 amino acids) that is cleaved into several other active peptides in the body, with various physiological effects, depending on where the peptide is processed.
POMC is mainly produced by the corticotroph cells of the anterior pituitary and the melanotroph cells of the intermediate pituitary. It is also produced in the hypothalamus, as well as the melanocytes in the skin.
In each of these tissues, the main cleavage products and downstream effects are as follows:
Anterior pituitary:
Adrenocorticotropic Hormone (ACTH): This is the main product of POMC in the anterior pituitary, and it plays a key role in the body’s response to stress, regulating cortisol release from the adrenal glands by binding to the ACTH receptor (also known as the melanocortin 2 receptor, MC2R). Cortisol, is often called the "stress hormone," and helps control blood sugar, regulate metabolism, reduce inflammation, and assist in memory formulation. It also has a significant role in controlling the salt and water balance in the body, influencing blood pressure.
Beta-lipotropin (β-LPH): This has a lesser role of POMC cleavage in the anterior pituitary compared to ACTH. Also, despite the name, this has little to do with lipid metabolism. It is another precursor peptide, which is further cleaved into:
β-endorphin: This is a potent endogenous opioid peptide, which binds to opioid receptors in the brain and nervous system, producing analgesia (pain relief), inducing feelings of well-being, and modulating the immune response.
γ-lipotropin (γ-LPH): which is cleaved further into Beta-Melanocyte Stimulating Hormone (β-MSH), which has a larger effect in the intermediate pituitary, described below.
Intermediate pituitary:
Alpha-Melanocyte Stimulating Hormone (α-MSH): This is the most important of the three melanocortin peptides in stimulating melanogenesis, which is responsible for pigmentation primarily of the hair and skin. It binds to melanocortin receptors, specifically MC1, MC3, MC4, and MC5, but not MC2, which is exclusive for ACTH. In addition to pigmentation, effects of binding to these receptors include control of feeding behavior (mainly MC4-R), regulation of the immune system and anti-inflammatory/antimicrobial properties, regulation of temperature, control of pain, behaviors involving sex, and learning.
Beta-Melanocyte Stimulating Hormone (β-MSH): This is one of the three types of melanocyte-stimulating hormones (MSH). β-MSH is mainly involved in regulating appetite and energy homeostasis via MC4 receptor (MC4-R) in the hypothalamus, which reduces appetite and feeding (α-MSH has a similar but lesser effect here). It also has effects on and pigmentation (although α-MSH has a greater effect here).
CLIP (Corticotropin-Like Intermediate Lobe Peptide): This peptide plays roles in modulating pancreatic exocrine function, modulating receptors for glutamate and GABA and effects on neurotransmission, along with other unclear effects.
Hypothalamus:
Here, POMC is processed into ACTH, α-MSH, and β-endorphin, which have been discussed above.
Skin (Keratinocytes and Melanocytes):
In human skin, POMC is expressed and processed into ACTH, α-MSH, and β-endorphin. This results in local stimulus of melanogenesis and pigmentation and appears to have have local immunomodulatory effects.
Control of POMC expression and release
POMC is controlled by a complex interplay of hormonal, neural, and circadian systems, and is affected by nutritional status, stress, sleep, and light/darkness exposure:
Hormonal Regulation
Corticotropin-Releasing Hormone (CRH) and Adrenocorticotropic Hormone (ACTH): CRH released from the hypothalamus stimulates the anterior pituitary to produce and secrete ACTH, a cleavage product of POMC. ACTH levels, in turn, provide a feedback loop to regulate CRH and POMC expression. CRH release is tied to circadian biology, which is regulated by the is regulated by the suprachiasmatic nucleus (SCN) in the brain.
Leptin: Produced by adipocytes, leptin acts on leptin receptors in the hypothalamus to stimulate POMC neuron activity, thereby increasing POMC expression. Leptin levels correlate with body fat mass and play a significant role in energy balance and appetite regulation.
Insulin: Similar to leptin, insulin can stimulate POMC neurons in the hypothalamus, contributing to the regulation of food intake and energy expenditure. Insulin levels, also reflect the body's nutritional status, influence POMC expression.
Neural Regulation:
Neurotransmitters and Neuropeptides: Various neurotransmitters and neuropeptides affect POMC activity, including GABA, glutamate, and neuropeptide Y. For practical purposes, this means that stress, sleep, and medications/supplements that affect neuronal activity can affect POMC.
Circadian Rhythm:
Light and Circadian Clock: POMC expression is also subject to circadian regulation, which is tied to light and darkness exposure throughout the 24-hour day. This topic alone is worthy of an entire future post, given recent interest in this topic.