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Melanocortin Receptors; emerging therapeutic targets?
Environments where high calorie foods are available with minimal physical cost are associated with an increased incidence of obesity and a cluster of metabolic abnormalities called the Metabolic Syndrome. Insulin resistance is the defining feature of the Metabolic Syndrome. Simply stated, energy intake and energy expenditure must be balanced over long periods to prevent excess weight gain and insulin resistance. Independently of adipose mass, the balance of fat consumption with oxidation in key insulin sensitive tissues is also thought to be important for weight maintenance and the prevention of insulin resistance. Faced with an epidemic of obesity and the Metabolic Syndrome, there is an urgent need to identify therapeutic targets that will reduce appetite, increase energy expenditure and/or fat oxidation, or a combination of both.
The melanocortin system is considered a promising target for the treatment of eating disorders and obesity.
The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis.
it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
Melanocortins are ancient peptides that are changed little throughout evolution, being traced back to the appearance of the first vertebrates. Lipton & Catania, 1997 J.M. Lipton and A. Catania, Anti-inflammatory actions of the neuroimmunomodulator alpha-MSH, Immunol Today 18 (1997), pp. 140-145. Article | PDF (366 K) | View Record in Scopus |Cited By in Scopus (254)They are derived from a larger precursor molecule known as the pro-opiomelanocortin (POMC) protein. This has been detected in the hypothalamus, pituitary and periphery including the immune system, spleen, lung, melanocytes and the gastrointestinal tract.
Hormones related to melanocortins
THE MELANOCORTIN SYSTEM consists of 1) the melanocortin peptides -, - and -melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH), 2) a family of five seven-transmembrane G protein-coupled melanocortin receptors, and 3) the endogenous melanocortin antagonists agouti and agouti-related protein (AGRP). The melanocortins are posttranslational products of the proopiomelanocortin (POMC) prohormone.
Of the five cloned melanocortin receptors, two (MC3R, MC4R) have been identified as important down stream effectors regulating energy homeostasis in response to neuropeptides secreted by POMC and AgRP neurons.
melanocyte stimulating hormone and other melanocortin peptides are inflammatory Agents. They are prod. Centrally and pheriphally and are released by activating membrane bound receptors. Melanocortin receptors are positively coupled to adenylyl cyclise, so activation leads to intracellular accumulation of the 2nd messenger cAMP.
There are 5 Receptors.
MC1R is the "classical" melanocyte -MSH receptor, expressed by cutaneous melanocytes, where it has a key role in determining skin and hair pigmentation. However, other cell types in the skin also express MC1R, including keratinocytes, fibroblasts, endothelial cells, and antigen-presenting cells. Its expressed by leukocytes, where it mediates the anti-inflammatory and immunomodulatory properties of melanocortins.
The function of MC2R in human adipose tissue is presently unclear. But Activation of the MC2R receptor leads to a regulation in the release of steroids by the adrenal cortex. Steroidgenesis A single study has shown that adipocytes of mice, but not human, express MC2R, so a potential role in metabolism might exist. A rare human autosomal recessive disorder, hereditary isolated glucocorticoid deficiency, is caused by mutations in MC2R.
MC3R is expressed in many areas of the CNS and in several peripheral tissues, including the gastrointestinal tract and placenta. Activation of MC3R in the heart has been shown to exhibit a protective effect in ischaemic-reperfusion injury. Thus MC3R could be proposed as a fine tuner of specific mechanisms operating during inflammation, cardiovascular function and energy homeostasis and metabolism.
A potential role in energy metabolism has been postulated for the MC3R since in MC3R null mice there is an increased fat mass and higher ratio of weight gain to food intake.
MC4R is solely expressed within many regions of the brain, including the hypothalamus, spinal cord and cortex. Many functions have been attributed to MC4R including erectile dysfunction and pain. However presently its an exciting target for controlling obesity.
The only firmly established function of MC5R, which was discovered by targeted deletion of that receptor, is its participation in exocrine function, particularly sebaceous gland secretion. It has the potential to be exploited for the treatment of skin disorders such as acne and dermatitis. found in the periphery and has been detected in tissues including the liver, lung, thymus, testis, ovary, mammary glands, fat cells, bone marrow, skin, skeletal muscle, stomach, and duodenum.
There is expression in B lymphocytes Buggy, 1998 J.J. Buggy, Binding of alpha-melanocyte-stimulating hormone to its G-protein-coupled receptor on B-lymphocytes activates the Jak/STAT pathway, Biochem J 331 (1998) (Pt 1), pp. 211-216. View Record in Scopus |Cited By in Scopus (59)and in T lymphocytes suggesting a role in immune regulation.
Appetite and melanocortins
Mutations in mc4r is the single most common gene causing human obesity. Drugs being developed are anti-obesity targets for the mc4r. in the 70s melanocortins Proved to reduce food intake when administered to animals.
The generation of mice lacking functional MC3R or MC4R has provided important tools for investigating specificity of action for novel melanocortin receptor agonists and antagonists, and in the general investigation of melanocortin receptor function.
The "yellow obese" mouse is another mutant strain that has been known for many years. Such mice develop adult-onset obesity, hyperinsulinemia, hyperglycemia, hyperphagia, and have a striking yellow color due to a mutation in the agouti gene. It turns out the the agouti protein binds with high affinity not only to the melanocortin-4 receptor (expressed in skin), but also to the melanocortin-4 receptor, which is expressed in the brain -involved in feeding behavior! stimulation of the melanocortin-4 receptor, inhibits feeding behavior.
POMC is potent agonist of Mc4R. During conditions of caloric excess, this rises leptin levels which then stimulates POMC and thus Mc4R which suppresses feeding.
Huszar et al study says Mc4R is necessary for regulation of body weight and appetite in mice, using mouse gene knockout technology
So Mc4r activation suppresses appetite but can also increase energy expenditure by nerve activity.
Melanocortins have a multitude of actions including: (i) modulating disease pathologies including arthritis, asthma, obesity; (ii) affecting functions, for example erectile dysfunction, skin tanning; and (iii) organ systems, for example cardiovascular system.
Melanocortins have multiple biological actions eg. They have a proactive effect on myocardial infarction in rats, colonic inflammation and ischemia-reperfusion injury. Other disease models have included mycobacterium induced arthritis.
The activation leads to inhibition of food intake and action of metabolic rate and skin pigmentation. Increasing evidence shows melanocortin peptides are potent modulators of inflammation. The melanocortin peptides play a protective role in maintaining homeostatic balance within the body.
Melanocortins have been implicated in many disease pathologies ranging from inflammation, obesity, cardiovascular and sexual health. Identification of receptors involved and the development of selective ligands have allowed for a greater understanding of their biological effects. Their ability to dampen down the host's response to inflammation, infection, ischaemia, etc., suggests that they play a protective role in maintaining a homeostatic balance within the body.
At present it is unclear whether peptide molecules could be first line therapeutics due to the rapid clearance and moderately short half-lives. However, given that they do not accumulate is of benefit so some of the side effects associated with conventional treatments may be avoided. It is possible that new receptors or subtypes may yet be discovered and allow for better pharmacological manipulation of disease states. With the development of orally active small molecule agonists directed at MCR, melanocortins could be useful as first line therapeutics in the treatment of many disease pathologies. What is clear is that we are entering an era where by promoting the body's own natural defenses could lead to novel therapeutics.
- It is possible that new receptors, ligands or subtypes may yet be discovered and allow for better pharmacological manipulation of disease states.
- Melanocortins have been implicated in many disease pathologies ranging from inflammation, obesity, cardiovascular and sexual health.
- Their ability to dampen down the host's response to inflammation, infection, ischaemia, etc., suggests that they play a protective role in maintaining a homeostatic balance within the body.
Pharmaceutical industry have developed small molecular for mc4r and there are already talks of the creation of a pill related to mc4r function that helps increase sexual function in men as well as making them thinner.
MC4-R is widely expressed in the CNS, mainly in the hypothalamus and brainstem. Disruption of this receptor causes an obesity syndrome characterized by moderate eating and obesity, mild hyperinsulinemia, increased linear growth, and otherwise relatively normal neuroendocrine function.
6% of Severely obese children in studies show pathogenic mutations in mc4r. They are obese and hyperphagic, show accelerated linear growth and sever hyperinsulinaemia.
We need to ask whether the mcr system effects common polygenic form forms of obesity, there is firm evident implying this, but some studies have shown links between POMC and obesity traits.
Its medically challenging to target the mc4r receptor because it is in brain , hard for accessibility. There are possible additional unknown functions that could results in unexpected side effects of the agonist.
There is still no drug to combat sever drug obesity to tackle the worldwide complications epidemic. IT must be designed safely.