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'''Melanocortins''' are peptides derived from [[pro-opiomelanocortin]] (POMC), determined by tissue-specific post-translational cleavage. The regulation of [[appetite]] involves a complex interplay between circulating hormones, neurotransmitters, neuropeptides and nutrients, and the melanocortin system is an important component of this. <ref>Cone R (2006) Studies on the Physiological functions of the melanocortin system ''Endocrine reviews'' [http://edrv.endojournals.org/cgi/content/full/27/7/736 27:736-49]</ref><ref>Qian G, Tamas H (2007) Neurobiology of feeding and energy expenditure ''Annu Rev Neurosci'' [http://www.annualreviews.org/doi/full/10.1146/annurev.neuro.30.051606.094324 30:367-98]</ref><ref>Seeley R ''et al.'' (2004) The critical role of The melanocortin system in the control of energy balance ''Annu Rev Nutrition'' [http://www.annualreviews.org/doi/full/10.1146/annurev.nutr.24.012003.132428?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed 24:133-49]</ref><ref>Mountjoy K (2010) Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes ''Biochem J''  [http://www.biochemj.org/bj/428/0305/4280305.pdf 428:305-24]</ref><ref>Fan W ''et al.'' (2000) The central melanocortin system can directly regulate serum insulin levels ''Endocrinology'' 141:3072-9</ref><ref>Gantz I, Fong TM (2003) The melancortin system ''Am J Physiol'' 284:E468-74</ref>


== Melanocortins and appetite ==
{{Image|MC4R PATHWAYS.JPG|centre|650px|Circulating molecules signal to the arcuate nucleus the nutritional state of the body}}


== Overview of Pro-opiomelanocortin (POMC) ==
POMC is expressed in many tissues including the [[pituitary gland]] and the [[brain]], and its products are involved in many different physiological processes. In the brain, POMC is expressed in the [[arcuate nucleus]] of the [[hypothalamus]] and the [[nucleus tractus solitarii]] (NTS) of the caudal brainstem, and products of POMC are important in appetite regulation. POMC was first noted for its importance in appetite and obesity in rodent studies. POMC-null mice exhibit [[hyperphagia]] and [[obesity]]. The suggestion that POMC has a role in [[appetite]] and energy balance is supported by studies on rare individuals with POMC mutations. In humans, a lack of POMC is generally fatal unless glucocorticoids are administered from birth as [[cortisol]] is essential for humans, but a few rare individuals with the mutation have shown very similar phenotype to the POMC knockout mouse. <ref>Oswal A, Yeo GSH (2007) The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics ''Obesity Rev'' 8:293–306</ref><ref>Farooqi IS, O’Rahilly S(2008) Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity. nature clinical practice ''Endocrinol Metabol'' </ref>
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.  
POMC expression in the arcuate nucleus is regulated by [[leptin]], a hormone secreted by adipose tissue. Both the [[opioid]] peptide [[B endorphin]] and the melanocortin [[alpha-melanocyte stimulating hormone]] (α-MSH) are cleaved from POMC; α-MSH is a very potent inhibitor of feeding behaviour, but β endorphin increases feeding behaviour (especially of highly palatable foods). It is therefore important to explore how the prohormone may be processed in different tissues and what dictates this. In the same sense, how are the cleavage enzymes regulated to produce various concentrations of the different peptide hormones? In the brain, the actions of α-MSH are mediated via specific melanocortin receptors - particulary MC3 and MC4 receptors. These receptors are unusual in that they have both endogenous agonists and antagonists.


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.  
==Agouti and agouti-related peptide==
The central melanocortin system involves several agonists such as α, β, γ MSH and two  inverse agonists, [[agouti]] and AgRP. These act on five subtypes of MC receptors (MCR1-5). <ref>Wikberga, J ''et al.'' (2000) New Aspects on the melanocortins and their receptors ''Pharmacol Res'' 42: 393-420</ref>
Of these, AgRP and α-MSH are thought to be most important for appetite regulation mainly via their actions on MC4 receptors.  In addition to suppressing appetite, α-MSH increases both metabolism and body temperature. <ref>Balasko ''et al.'' (2010) Central alpha-MSH, energy balance, thermal balance and antipyresis ''J Thermal Biol'' 35:211-7
</ref>Some MC4 receptors have been found on adipocytes, suggesting that circulating melanocortins may also be involved in regulating energy homeostasis.  


Agouti is an antagonist at MC1 and MC4 receptors, while AgRP iis an inverse agonist at MC3 and MC4 receptors. Mutant mice with ectopic expression of these peptides are hyperphagic with an increase in adipose mass, lean mass, and hyperinsulinemia. <ref>Pritchard L ''et al.''(2002) Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity ''J Endocrinol'' [http://joe.endocrinology-journals.org/cgi/reprint/172/3/411 172:411-21]</ref>


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


{{Image|POMC.JPG|centre|700px|The breakdown of POMC by prohormone convertase enzymes (PC1 and PC2) into melanocortins and B-endorphin}}


=== melanocyte-stimulating hormones and their receptors ===
PC1 and PC2 are expressed in cells other than POMC cells and have important physiological functions other than POMC cleavage. For example, PC1 is essential for the biosynthesis of [[insulin]] and PC2 for the biosynthesis of [[glucagon]]. However, transgenic mice deficient in PC2 (PC2 'knockout' mice) exhibit no α-MSH expression at all, and [[Prader Willi]] patients have reduced hypothalamic PC2 expression. <ref>Millington ''et al.'' (2003)</ref>  The PC2 knockout mice are so defective in other ways that it is hard to tell whether the lack of alpha MSH has an effect.<ref>Scamuffa ''et al.'' (2006)</ref>  Prader Willi sufferers exhibit an obese phenotype but again this syndrome comes as a result of a mutation of several genes so it cannot be inferred that PC2 mutation is solely responsible for the obese and hyperphagic phenotype.  
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==   
Leptin-deficient mice show an upregulation of POMC and PC2 expression.   
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.  
=== Melanocortin receptors ===
{{Image|Melanocortin receptors.JPG|right|500px|'''Melanocortin receptors'''}}
The melanocortin system encompasses a number of CNS circuits including
#α-MSH -containing neurons of the arcuate nucleus.
#POMC neurons in the [[nucleus of the solitary tract]] (NTS)
#AgRP- containing neurones of the arcuate nucleus. AgRP is an inverse agonist at MC4 receptors, thus opposes the actions of α-MSH. AgRP is co-expressed by the orexogenic neurons that make [[neuropeptide Y]] (NPY). MC4 agonists reduce food intake and increase energy expenditure, thus reducing body weight, wheras MC4 antagonists enhance food intake (hyperphagia) and decrease energy expenditure, and thus increase body weight.
                     
Although the melanocortin system is 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.


Agonists Antagonists
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 melanocortin agonists can’t bind to melanocortin receptors to suppress appetite. 
Reduce food intake Enhance food intake (hyperphagia)
Increase energy expenditure Decrease energy expenditure
Reduce body weight Increase body weight


Leptin secreted from [[adipose tissue]] and insulin secreted from the [[pancreas]] also regulate food intake, in part by their actions on the melanocortin systems. Excess adipose tissue (in obese individuals) results in an increase in leptin production, which normally induces a feeling of satiety, but excess production of NPY (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.


'''Insulin'''
After a meal, there is a dramatic increase in insulin levels, some of which crosses the blood-brain barrier in a concentration that is representative of circulating insulin levels. Central administration of insulin acts on both NPY and POMC systems, and increases POMC mRNA synthesis as well as inhibiting food intake in fasting rats. Rats with untreated diabetes have a diminished amount of POMC mRNA, which is indicative of its involvement in stimulating its synthesis.


'''Ghrelin'''
[[Ghrelin]] stimulates arcuate nucleus production of NPY and AgRP, while inhibiting the suppressive effects that leptin induces on appetite. Ghrelin administration in rats produces hyperphagia and increased body weight. Central administration of ghrelin results in excessive eating, accompanied by increased arcuate NPY and AgRP expression.


 
'''Thyroid hormone'''
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.
MC4R is expressed in a variety of neuronal cell types, including the [[thyrotropin-releasing hormone]] (TRH) neurones of the PVN, consistent with a role in metabolism and thus energy homeostasis. Inhibitory feedback from [[thyroxin]]'s (T4) biologically active derivative [[triodothyronine]] (T3)is occurring at the MC4R <ref>Decherf S ''et al.'' (2010) Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression ''PNAS'' 107:4471–6</ref>.This incidentally alleviates inhibition of food intake and allows the activation of orexigenic pathways. The negative feedback is strongest in the brainstem region where it is thought to regulate meal size and [[thermogenesis]].
 
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.  
 
== Animal models and human examples of defects in the melanocortin system ==
=== Experimental evidence and methods used to investigate melanocortin ===
 
== suggested future studies ==
 
== Discussion ==
 
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Melanocortins are peptides derived from pro-opiomelanocortin (POMC), determined by tissue-specific post-translational cleavage. The regulation of appetite involves a complex interplay between circulating hormones, neurotransmitters, neuropeptides and nutrients, and the melanocortin system is an important component of this. [1][2][3][4][5][6]

Circulating molecules signal to the arcuate nucleus the nutritional state of the body

POMC is expressed in many tissues including the pituitary gland and the brain, and its products are involved in many different physiological processes. In the brain, POMC is expressed in the arcuate nucleus of the hypothalamus and the nucleus tractus solitarii (NTS) of the caudal brainstem, and products of POMC are important in appetite regulation. POMC was first noted for its importance in appetite and obesity in rodent studies. POMC-null mice exhibit hyperphagia and obesity. The suggestion that POMC has a role in appetite and energy balance is supported by studies on rare individuals with POMC mutations. In humans, a lack of POMC is generally fatal unless glucocorticoids are administered from birth as cortisol is essential for humans, but a few rare individuals with the mutation have shown very similar phenotype to the POMC knockout mouse. [7][8]

POMC expression in the arcuate nucleus is regulated by leptin, a hormone secreted by adipose tissue. Both the opioid peptide B endorphin and the melanocortin alpha-melanocyte stimulating hormone (α-MSH) are cleaved from POMC; α-MSH is a very potent inhibitor of feeding behaviour, but β endorphin increases feeding behaviour (especially of highly palatable foods). It is therefore important to explore how the prohormone may be processed in different tissues and what dictates this. In the same sense, how are the cleavage enzymes regulated to produce various concentrations of the different peptide hormones? In the brain, the actions of α-MSH are mediated via specific melanocortin receptors - particulary MC3 and MC4 receptors. These receptors are unusual in that they have both endogenous agonists and antagonists.

Agouti and agouti-related peptide

The central melanocortin system involves several agonists such as α, β, γ MSH and two inverse agonists, agouti and AgRP. These act on five subtypes of MC receptors (MCR1-5). [9] Of these, AgRP and α-MSH are thought to be most important for appetite regulation mainly via their actions on MC4 receptors. In addition to suppressing appetite, α-MSH increases both metabolism and body temperature. [10]Some MC4 receptors have been found on adipocytes, suggesting that circulating melanocortins may also be involved in regulating energy homeostasis.

Agouti is an antagonist at MC1 and MC4 receptors, while AgRP iis an inverse agonist at MC3 and MC4 receptors. Mutant mice with ectopic expression of these peptides are hyperphagic with an increase in adipose mass, lean mass, and hyperinsulinemia. [11]


(PD) Image: Jessica Ivy
The breakdown of POMC by prohormone convertase enzymes (PC1 and PC2) into melanocortins and B-endorphin

PC1 and PC2 are expressed in cells other than POMC cells and have important physiological functions other than POMC cleavage. For example, PC1 is essential for the biosynthesis of insulin and PC2 for the biosynthesis of glucagon. However, transgenic mice deficient in PC2 (PC2 'knockout' mice) exhibit no α-MSH expression at all, and Prader Willi patients have reduced hypothalamic PC2 expression. [12] The PC2 knockout mice are so defective in other ways that it is hard to tell whether the lack of alpha MSH has an effect.[13] Prader Willi sufferers exhibit an obese phenotype but again this syndrome comes as a result of a mutation of several genes so it cannot be inferred that PC2 mutation is solely responsible for the obese and hyperphagic phenotype.

Leptin-deficient mice show an upregulation of POMC and PC2 expression.

Melanocortin receptors

(PD) Image: Jessica Ivy
Melanocortin receptors

The melanocortin system encompasses a number of CNS circuits including

  1. α-MSH -containing neurons of the arcuate nucleus.
  2. POMC neurons in the nucleus of the solitary tract (NTS)
  3. AgRP- containing neurones of the arcuate nucleus. AgRP is an inverse agonist at MC4 receptors, thus opposes the actions of α-MSH. AgRP is co-expressed by the orexogenic neurons that make neuropeptide Y (NPY). MC4 agonists reduce food intake and increase energy expenditure, thus reducing body weight, wheras MC4 antagonists enhance food intake (hyperphagia) and decrease energy expenditure, and thus increase body weight.

Although the melanocortin system is 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.

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 melanocortin agonists can’t bind to melanocortin receptors to suppress appetite.

Leptin secreted from adipose tissue and insulin secreted from the pancreas also regulate food intake, in part by their actions on the melanocortin systems. Excess adipose tissue (in obese individuals) results in an increase in leptin production, which normally induces a feeling of satiety, but excess production of NPY (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.

Insulin After a meal, there is a dramatic increase in insulin levels, some of which crosses the blood-brain barrier in a concentration that is representative of circulating insulin levels. Central administration of insulin acts on both NPY and POMC systems, and increases POMC mRNA synthesis as well as inhibiting food intake in fasting rats. Rats with untreated diabetes have a diminished amount of POMC mRNA, which is indicative of its involvement in stimulating its synthesis.

Ghrelin Ghrelin stimulates arcuate nucleus production of NPY and AgRP, while inhibiting the suppressive effects that leptin induces on appetite. Ghrelin administration in rats produces hyperphagia and increased body weight. Central administration of ghrelin results in excessive eating, accompanied by increased arcuate NPY and AgRP expression.

Thyroid hormone MC4R is expressed in a variety of neuronal cell types, including the thyrotropin-releasing hormone (TRH) neurones of the PVN, consistent with a role in metabolism and thus energy homeostasis. Inhibitory feedback from thyroxin's (T4) biologically active derivative triodothyronine (T3)is occurring at the MC4R [14].This incidentally alleviates inhibition of food intake and allows the activation of orexigenic pathways. The negative feedback is strongest in the brainstem region where it is thought to regulate meal size and thermogenesis.

References

  1. ↑ Cone R (2006) Studies on the Physiological functions of the melanocortin system Endocrine reviews 27:736-49
  2. ↑ Qian G, Tamas H (2007) Neurobiology of feeding and energy expenditure Annu Rev Neurosci 30:367-98
  3. ↑ Seeley R et al. (2004) The critical role of The melanocortin system in the control of energy balance Annu Rev Nutrition 24:133-49
  4. ↑ Mountjoy K (2010) Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes Biochem J 428:305-24
  5. ↑ Fan W et al. (2000) The central melanocortin system can directly regulate serum insulin levels Endocrinology 141:3072-9
  6. ↑ Gantz I, Fong TM (2003) The melancortin system Am J Physiol 284:E468-74
  7. ↑ Oswal A, Yeo GSH (2007) The leptin melanocortin pathway and the control of body weight: lessons from human and murine genetics Obesity Rev 8:293–306
  8. ↑ Farooqi IS, O’Rahilly S(2008) Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity. nature clinical practice Endocrinol Metabol
  9. ↑ Wikberga, J et al. (2000) New Aspects on the melanocortins and their receptors Pharmacol Res 42: 393-420
  10. ↑ Balasko et al. (2010) Central alpha-MSH, energy balance, thermal balance and antipyresis J Thermal Biol 35:211-7
  11. ↑ Pritchard L et al.(2002) Pro-opiomelanocortin processing in the hypothalamus: impact on melanocortin signalling and obesity J Endocrinol 172:411-21
  12. ↑ Millington et al. (2003)
  13. ↑ Scamuffa et al. (2006)
  14. ↑ Decherf S et al. (2010) Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression PNAS 107:4471–6
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