Melanocortins and appetite

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Overview of Pro-opiomelanocortin (POMC)

POMC is pro-opiomelanocortin and is an important pro-hormone that gives rise to an array of bioactive peptide hormones that are implicated in energy balance, stress responses, pain, immune modulation satiety, pigmentation and even exocrine gland secretions. It is expressed in the pituitary gland, skin, immune system and brain. In the brain it is expressed in the arcuate nucleus of the hypothalamus (ARH). POMC is post-translationally cleaved by a complex set of enzymes into a variety of hormones (see fig 1).

POMC was first noted for its importance in appetite and obesity in rodent studies. POMC-null mice were seen to exhibit phenotype of hyperphagia and obesity without insulin resistance. Their adrenal gland was also atrophic and glucocorticoid levels were undetectable. We can imagine this is as a result of a lack of ACTH stimulating adrenal cell secretion andproliferation. This suggestion that POMC has a role in energy balance was supported by studies on rare individuals with POMC mutations. In humans a lack of POMC is fatal unless glucocorticoids are administered from birth as cortisol is essential for humans. A few rare individuals with the mutation have shown very similar phenotype to the knock out mouse.

While these studies show that POMC-derived hormones may have a role in energy balance they don’t tell us which peptides are responsible for the effects and furthermore the lack of adrenal hormones as a secondary result of POMC lack may overshadow the primary POMC effects. Therefore we are required to look at the peptides in more detail. The main system implicated in energy balance is the MELANOCORTIN SYSTEM.

COULD GO ON ABOUT THE TRIGGERS FOR POMC PRODUCTION: ENZYMES IN CLEAVAGE LEPTIN, INSULIN, CCK ETC- I think pretty interesting.

melanocyte-stimulating hormones and their receptors

This is made up of several endogenous agonists such as alpha, beta, gamma MSH and interestingly has two endogenous antagonists as well namely the AgRP and agouti. These act on 5 different subtypes of the MCR (MCR1-5). See table…

The Melanocortin Pathway

The control and regulation of feeding involves a complex interplay between a number of circulating hormones, neurotransmitters and nutrients, and the Melanocortin system has been identified as being a central component. The melanocortin system is the name collectively given for; ►Neurons arising in the arcuate nucleus of the hypothalamus, and express AgRP,NPY or POMC. ►POMC neurons that project to the brainstem ►Melanocortin receptors, predominately MC3R and MC4R that respond to POMC peptides and AgRP. In addition to its involevement in regulating energy homeostasis, the Melancortin system plays a role in mediating a number of physiological processes within the body including (3)

Although the Melanocortin system is known to be central to the regulatory mechanisms controlling appetite and satiety, the precise mechanism is not fully understood. Complexity arises from both the direct and indirect effects of a number of compounds including leptin, insulin, glucose, ghrelin, NPY, serotonin, peptide YY and endorphin, all of which act in isolation and in sync to mediate their effects on these POMC neurons.

Below is a table showing the opposing effects that POMC agonists and antagonists have on feeding behaviour.

Agonists Antagonists Reduce food intake Enhance food intake (hyperphagia) Increase energy expenditure Decrease energy expenditure Reduce body weight Increase body weight

This highlights the role of the melanocortin system in regulating energy homeostasis, and why disruption in the genes controlling this system, i.e. genetic mutations of the system, can result in individuals which are hyperphagic and consequentially obese.

A number of mutations of this system have been identified in mice, all of which show a dysregulation in energy homeostasis. Many of the mutations discovered involve excess production of POMC antagonists, so that POMC agonists can’t bind to POMC receptors in order to suppress appetite.

1) Excess production of the agouti protein induces its’ antagonistic effects through binding to both the MC1R and MC4R. 2) An increase in the expression of AGRP which functions by antagonising receptors MC3R and MC4R. This prevents the potent appetite suppressor alpha MSH from binding. 3) A mutation which results in a deficiency in the number of MC4R receptors. 4) The insufficient production of POMC derived peptides to bind to these receptors. Obese individuals have presented with POMC deleterious gene mutations, as well heterozygous mutations in the MC4R receptor. .

POMC neurons and their peptides mediate satiety signals, while NPY neurons induce hunger signals with decreased energy expenditure. The median eminence of the arcuate nucleus receives projections from both POMC and NPY neurons, highlighting its role in controlling both energy expenditure as well as hunger/satiety signals. 
This integration involves both long term signals (leptin from adipose tissue and insulin), as well as acute hunger/satiety signals from the brainstem. 

The melancortin Alpha MSH has been identified as one of the most important regulators of energy homeostasis in the hypothalamus, where it induces a state of satiety within an individual through its actions on the MC4R. Additionally, administration of ACTH into certain regions of the hypothalamus has similar effects. Agouti is an antagonist at MC1R and MC4R receptors, while AGRP incurs antagonistic effects through its action on MC3R and MC4R receptors. Due to suppression of the alpha MSH anorectic signal, mutant mice with ectopic expression of these peptides are hyperphagic with an increase in adipose mass, lean mass, hyperinsulinemia and consequentially are clinically obese.

Role of Leptin and Insulin

Leptin released form adipose tissue and insulin from the pancreas, also serve to regulate food intake. Excess adipose tissue (i.e. as occurs in obese individuals) results in an increase in leptin production (which normally induces a feeling of satiety), but excess production of NPY peptides (as occurs in some mutations of the melancortin system), can suppress its effects. Similarly insulin levels show a marked increase in obese individuals, with hyperinsuliemia being one of the first metabolic disturbances identified in those obese subjects with mutations of the melanocortin system.

Ghrelin The role of the potent appetite stimulant within the melanocortin system has been verified, whereby central administration of this peptide results in excessive eating, but if NPY antagonists are given in conjunction,a state of hyperphagia is not induced. During periods of meal deprivation, Ghrelin levels increase. They induce their potent appetite stimulating properties by activating arcuate NPY and AgRP expression. In contrast, following food consumption, ghrlein levels show a marked decrease.

An example of the complexity that arises in fully understanding the precise mechanism governing this system arises from mice AgRP KO models. Interestingly, while the involvement of AgRP in the melanocortin system is undisputed, one would expect such KO to present with altered phenotypes and eating patterns, yet these AgRP were just like their wild type counterparts.

Although Peptide YY has been identified as an appetite suppressor, it appears to mediate its effects through a distinct pathway that does not involve the melanocortin system as both POMC and MC4R KO continued to show a decrease in food intake following its administration, indicating that another system may be involved. This further highlights the complexity of the mechanisms controlling energy homeostasis.

Discussion

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