POMC (Proopiomelanocortin)

The sensations of hunger and satiety, which is the feeling of fullness after a meal, are regulated in the hypothalamus and pituitary of the brain. Proteins called neuropeptides are expressed by specific groups of neurons in these regions of the brain. Each of these neurons interacts with each other to control the response to hunger or satiety. Neurological or genetic defects in these neuropeptides or their respective precursors can lead to obesity, as was seen in knockout mice who were genetically manipulated such that they do not express the gene called proopiomelanocortin (POMC).

POMC is a protein expressed in the arcuate nucleus of the hypothalamus and is the precursor to nine biologically active peptides. Several of these are neuropeptides that play a vital role in regulating the response to hunger and satiety. This protein is a precursor to neuropeptides called melanocortins, specifically alpha-melanocortin (alpha-MSH) secreting hormone, beta-melanocortin (beta-MSH) secreting hormone, and gamma-melanocortin (gamma-MSH) secreting hormone. These neuropeptides decrease energy intake and increase energy expenditure, that is, prevent the body from gaining weight by increasing its metabolism. They do so by binding to five receptors called G-protein coupled receptors where an effect is initiated and completed within the cell using secondary signaling proteins.

Melanocortin-coupled receptor 3 (MCR-3) and melanocortin-coupled receptor 4 (MCR-4) are highly expressed in the central nervous system and are the most important in maintaining the balance between energy intake and expenditure. More focus has been placed on the melanocortin-coupled receptor 4 being that it has been previously shown to play a larger role in energy homeostasis. Mice and humans who lack this receptor are obese and hyperphagic, eating [Page 615]frequently compared to people who have this receptor. Alpha- and beta-MSH bind to the MCR-4 receptor with higher affinity than gamma-MSH, thus this pathway has been investigated in more detail.

In addition, mutations in the MCR-4 receptor and POMC results in severe obesity due to increased energy intake and reduced energy expenditure, the opposite of what they normally do to the body. Recently, a specific genetic mutation in the region of POMC that expresses beta-MSH was found to be more common in obese subjects in a small clinical study. Mutations in the POMC gene were screened in 538 Caucasian subjects from the United Kingdom with severe early-onset obesity. The mutation was a change in the amino acid tyrosine to cysteine that alters the three-dimensional structure of the protein, reducing the ability of the protein to bind to its receptor and facilitate its action in the body. As a result of this study, the POMC gene expresses neuropeptides that maintain energy intake and expenditure to prevent the onset of obesity.