Melanotan II, sometimes written Melanotan 2, also called MT-II, MTII, MT2, or MT-2, is a hypothalamic hormone that belongs to the melanotropin family, a group of peptides that react with the melanocortin receptor (MC-R) family and exert a wide and important range of effects in nearly all types of tissue. Other hormones in the melanotropin family include ACTH and alpha-melanocyte stimulating hormone. MT-II is an analog of a-MSH that is structurally altered to reduce enzymatic degradation and enhance receptor binding. It was originally studied for its tanning and pigmentation properties but more recent research has focused on antioxidant properties, circadian rhythm entrainment, possible use as a therapy for erectile dysfunction or other arousal disorders, and as a research tool to highlight the factors that lead to obesity, insulin resistance, inflammation, and other types of dysfunction. The melanocortin system is an important therapeutic target and MT-II is a broad and powerful stimulator of MC-R action.
The Melanocortin System
MC-Rs (Melanocortin receptors)
Melanocortin receptors are the primary mechanism through which MT-2 exerts its action. MC-Rs or melanocortin receptors exist in a variety of tissues and have divergent functions in humans as well as many other organisms. Collectively the MC-Rs, which consist of various sub-types with diverse functions, comprise the melanocortin system. The melanocortin system is pleiotropic (exerting different functions throughout the body, using different mechanisms, based upon a limited or conserved number of functional groups or ligands) exerts profound systemic effects in its central and peripheral interaction with other prominent functional neuropeptide-based systems (leptin, ghrelin, insulin, etc).
Recorded functions include control of energy balance via central and peripheral mechanisms, central and peripheral thyroid function, central and peripheral response to insulin, a primary role in skin pigmentation, effects on reproductive function both physically and behaviorally, modulation of pain and neural sensitivity in conjunction with endogenous opioids, participation in inflammation response, neuroprotective properties (including resistance to oxidative stress), aggressiveness, and modulation of circadian rhythms including excitatory anticipation of food intake.
The seemingly disparate effects of the melanocortin system are hypothesized to be correlated in individuals due to common action of the melanocortin peptides on five different receptors (Roulin, 2011). MC-Rs are G-coupled protein receptors found throughout the body in nervous tissue, skeletomuscular, and adipose tissues as well as digestive tissue and various major organs (Juan, 2007)
Of the five different receptors that have been identified, the MC(1) or MC-1R is perhaps the best-studied. MC-1R plays a role in pigmentation by regulating production of brown and black eumelanic pigments from melanocytes (Roulin, 2011); Roulin writes that in some animal models;
“the degree of eumelanin production may, in some cases, be associated with the regulation of glucocorticoids, immunity, resistance to oxidative stress, energy homeostasis, sexual activity, and aggressiveness.”
MC2-R, also known as the ACTH receptor, is found on the adrenocortex and in adipocyte cells (Getting, 2000). The peptide ACTH(1-24) was successful in reducing tumor weight when applied for 20 days in a study designed to test efficacy of treatment of MC2-R positive tumors (Zwermann, 2005).
MC3-R appears to mediate the metabolism of fatty acids within adipocytes (fat cells) but not muscle tissue (Juan, 2007). It is also expressed within the pancreas, hypothalamus, and GI tract, likely due to its dual role of melanocortins as signaling hormones and peripheral mediators of metabolic action (Juan, 2007).
MC4-R is found throughout the brain, the nervous system, and also in skeletal muscle tissue (Juan, 2007). MC4-R appears to regulate thyroid hormone response to fasting and food intake, which Vella et al point out is an “adaptive response” to periods of reduced energy consumption (2011).
In an animal model, Vella et al demonstrated that MC4R agonism is required for hepatic T4-to-T3 conversion (T3 being the more active thyroid hormone that is converted in the liver from the less-active T4 form), and plays an important role in the feedback signaling pathway involved in fasting-induced suppression of thyroid action:
To evaluate the role of these pathways in vivo, we developed double knockout mice that lack both the melanocortin 4 receptor (MC4R) and NPY. We show that NPY is required for fasting-induced suppression of Trh expression in the PVN. However, both MC4R and NPY are required for activation of hepatic pathways that metabolize T(4) during the fasting response. Thus, these signaling pathways play a key role in the communication of fasting signals to reduce thyroid hormone levels both centrally and through a peripheral hepatic circuit (Vella, 2011).
Xi et al (2011) found in a meta-analysis of data spanning approximately 120,000 subjects that two MC4R polymorphisms are associated with obesity.
MC5-R is directly involved in fatty acid oxidation (FAO) metabolic pathway regulation in skeletal muscle tissue; Juan (2007) found that:
"[a]fter a-MSH treatment, carnitine palmitoyltransferase-1 and fatty acid oxidation (FAO) increased in a dose-dependent manner. A strong melanocortin agonist, NDP-MSH, also stimulated FAO in primary culture muscle cells and C2C12 cells"
In other words, administration a-MSH and its agonists (including MT-II) increases fat oxidation in muscle tissue. Juan also reported (2007) that a selective MC3R and MC4R receptor did not effectively stimulate fatty acid oxidation. Through deduction and application of other agonists and antagonists, Juan determined that the MC5R plays a crucial role in the melanocortin system’s regulation of fatty acid oxidation (2007).
MC-Rs and Energy Balance: Regulation of Food Intake and Bodyweight
Melanocortin System and Obesity
Dysfunction and/or alteration of the melanocortin system – disruption of feedback mechanisms, reduced or altered profiles of gene expression, and other phenomena, some linked to specific polymorphisms and others thought to be linked to environment – are correlated with obesity (Hoch et al, 2007). As such, the melanocortin system is a potential therapeutic target, and certain agonists in particular (those with activity at MC-3r, MC-4r, and MC-5r) hold promise for reduction of appetite, decreased bodyweight, increased fatty acid oxidation, and improvements in obesity-related disease states such as insulin resistance, diabetes, and high blood pressure.
Hoch et al analyzed human fatty tissue samples from obese and control subjects and found altered expression levels of every melanocortin receptor in the samples from obese subjects:
"Notable expression was found for MC1-R, whereas no mRNA for MC2-R and MC3-R was detected; MC4-R and MC5-R mRNA was occasionally detectable but at very low levels. MC1-R mRNA in subcutaneous fat was increased in obese patients as compared with controls; omental fat of both groups had slightly higher MC1-R expression than subcutaneous fat and did not differ between patient groups. Immunohistochemical analysis of the MC1-R in adipose tissue sections showed that MC1-R expression was higher in macrophages but also present in adipocytes. The expression of MC1-R and the lack of MC2-R in human adipose tissues indicate that the melanocortins may regulate cell proliferation and/or inflammatory signals rather than lipolysis. Also, the increased expression of MC1-R in subcutaneous fat of obese subjects may reflect one aspect of the pathophysiology of obesity. (Hoch et al, 2007)"
Alpha-melanocyte stimulating hormone, of which Melanotan 2 is an analog, is the primary endogenous stimulator of the melanocortin system in humans; a-MSH is stimulated by leptin (Soos et al, 2011). The production of, and sensitivity to leptin is typically impaired in obese subjects (Roth et al, 2008).
One pilot study found similar levels of a-MSH when comparing obese and normal subjects (Baltazi et al, 2011), but it is possible that the methods used were not sensitive enough. Levels of Neuropeptide Y were higher in obese subjects. If the study’s findings prove correct, it is possible that levels of NPY and leptin interact with a-MSH and MC-R receptors to determine a-MSH function, or it is possible that the altered expression of MC-R receptors (as well as different polymorphisms associated with obesity) discussed previously is responsible for the differences in function between obese and normal subjects.
Soos et al found that despite resistance to the effects of leptin, obesity does not necessarily entail resistance to the effects of a-MSH:
“With increasing BW, resistance develops to leptin-induced anorexia, but independent of this, in genetically modified animals, some alpha-MSH actions were maintained” (2011)."
The responsiveness to a-MSH in obese states demonstrated by Soos et al is a good indication of the potential for a-MSH or its analogs, such as MT-II, to treat obese states by bringing about reductions in bodyweight, restoring of central and peripheral sensitivity to other hormones (e.g. thyroid hormones), and reducing hunger:
We investigated the responsiveness of the MC system in its complexity (FI vs. metabolic correlates) in genetically intact male Wistar rats of different nutritional states (and different leptin sensitivities), i.e., in rats aged 2 months [normally fed (NF2)] or 6 months [calorie-restricted (CR6), fed ad libitum (NF6), and high-fat diet-induced obese (HF6) groups]. A 7-day-long, 1-μg/μl/h intracerebroventricular infusion of alpha-MSH reduced BW in all groups, particularly in NF6 and NF2 animals, and even CR6 rats lost BW upon alpha-MSH infusion (in contrast to leptin administration). Anorexia developed in NF2-NF6 and less in CR6 groups, and some FI fall was also seen in HF6 rats. The hypermetabolic effects (temperature/heart rate elevations) were most pronounced in CR6 and next in HF6 rats. These data suggest that alpha-MSH responsiveness is maintained in various forms (depending on nutritional state), despite obesity-induced leptin resistance. (2011)
Results from Silva et al (2005) also lead the authors to conclude that a-MSH resistance is not likely in obese states and that a-MSH analogs are a promising treatment for obesity:
"After a 5-day control period, rats were infused with MC3/4-R agonist melanotan II (10 ng/h, ICV), for 10 days followed by a 5-day recovery period. HF rats were heavier (558+/-21 versus 485+/-13 g) with 140% more visceral fat than NF rats, hyperleptinemic (8.9+/-0.5 versus 2.7+/-0.5 ng/mL), and insulin resistant. HF rats also had higher MAP (109+/-3 versus 100+/-1 mm Hg). Chronic melanotan II infusion significantly increased MAP in HF and NF (7+/-2 and 6+/-1 mm Hg), decreased caloric intake (-32+/-2 and -25 +/-2 kcal/day), and reduced insulin levels in both groups by approximately 50%. Thus, the metabolic and cardiovascular actions of chronic MC3/4-R activation are preserved in diet-induced obesity, supporting a potential role for the hypothalamic melanocortin system in obesity hypertension."
Additionally, the hypertensive and cardiovascular diseases associated with obesity may also be treatable with a-MSH analogs or other MC3/4-R activators (Silva, 2005).
Melanocortin System and Inflammation
Getting writes that while MC1-R and MC2-R are well characterized, MC3, -4, and -5r are not; MC3-r is reported (2000) to have a role in models of experimental inflammation. ACTH-4-10 acts on rat MC3-R receptors and inhibits of cytokine formation and neutrophil migration (Getting, 2000). Other selective MC3-R agonists confirm the immunomodulatory properties of the melanocortin-3 receptor.
Getting et al report that MC3-R agonism shows efficacy in gouty arthritis and point to evidence that MC3-R agonists are likely to work in other systemic inflammatory disorders as well (2000).
In a separate study Getting et al (2001) report that Melanotan ii has anti-inflammatory action at the MC3R receptor.
Melanotan II was originally studied for its pigmentation effects (Hadley, 2005), which are mediated by activity at the MC1-R receptor. The accidental discovery that MT-II also has erectogenic and libidogenic properties in men and women has led to broader study of MT-II for treatment of sexual dysfunction, but the pigmentation effects are perhaps the best-known property of MT-II (Kadekaro and Abdel-Malek, 2007).
Melanotan 2 may, upon approval, provide a “therapeutic tanning” benefit to at-risk groups (Hadley and Dorr, 2006); melanin expression resulting in darker pigmentation is associated with reduced risk of various skin cancers and reduced sun damage from UV rays.
In addition to the chronic but dramatic darkening of pigmentation, a-MSH analogs including MT2 also offer immediate UV protection through a direct antioxidant effect after pretreatment before sun/UV exposure (Song et al, 2009).
UV exposure directly results in DNA damage:
Exposure of cultured human melanocytes to ultraviolet radiation (UV) results in DNA damage. In melanoma, UV-signature mutations resulting from unrepaired photoproducts are rare, suggesting the possible involvement of oxidative DNA damage in melanocyte malignant transformation (Song et al, 2009).
Song et al provide “unequivocal evidence for induction of oxidative DNA damage by UV in human melanocytes and reduction of this damage by alpha-MSH”:
"Here we present data demonstrating immediate dose-dependent generation of hydrogen peroxide in UV-irradiated melanocytes, which correlated directly with a decrease in catalase activity. Pretreatment of melanocytes with alpha-melanocortin (alpha-MSH) reduced the UV-induced generation of 7,8-dihydro-8-oxyguanine (8-oxodG), a major form of oxidative DNA damage. Pretreatment with alpha-MSH also increased the protein levels of catalase and ferritin. The effect of alpha-MSH on 8-oxodG induction was mediated by activation of the melanocortin 1 receptor (MC1R), as it was absent in melanocytes expressing loss-of-function MC1R, and blocked by concomitant treatment with an analog of agouti signaling protein (ASIP), ASIP-YY. (2009)"
The reduction in oxidative damage is unrelated to melanin production (Kadekaro et al, 2003) but a red-haired gene is associated with reduced response by MC1R to a-MSH (and therefore, MT-II) in reducing UV damage.
Libido and Erectogenic Effects
In men and women, a-MSH and MTII precipitate acute sexual arousal, increases in libido, and (in males) increases in erection parameters (Wessells et al, 2000). This effect was originally noticed while studying the phenomenon of MT-II induced tanning (Hadley, 2005).
Wessells et al noted an increase in erection duration in men (defined as 80% or greater tip rigidity) of approximately 45 minutes, versus approximately 2 minutes for controls when men were given a dose of 0.025mg/kg (2000).
MT-II is effective in psychogenic ED as well as other types of ED:
The erectogenic properties of Melanotan ii are not limited to cases of psychogenic erectile dysfunction; men with a variety of organic risk factors developed penile erections. The finding of increased sexual desire warrants further investigation of centrally acting agents on disorders of sexual desire. (Wessells et al, 2000).
Hadley (2005) notes that since MT-II works primarily at the level of the brain, it is more broadly effective in treating arousal disorders, and precipitates genital arousal and libido increases in women as well as men. However, a different study (Vemulpalli et al, 2001) found that neuronal release of NO is partially responsible for the erectile properties of MT-II:
"Intravenous injection of MT-II (66 and 133 microg kg(-1) elicited dose-related increases in cavernosal pressure…. The role of NO-cyclic GMP dependent pathway to MT-II-induced increases in cavernosal pressure was investigated by bilateral transection of the pudendal nerves and by inhibition of NO synthase with L-NAME (20 mg kg(-1), i.v. over 30 min). Ablation of the pudendal nerves or pretreatment with L-NAME abolished the MT-II-induced increases in intracavernosal pressure in anaesthetized rabbits. 6. The data suggest that activation of central melanocortin receptors by MT-II increases cavernosal pressure by the neuronal release of NO."
The broad action on multiple pathways to both facilitate and induce erection and sexual arousal by MT-II (Giuliano et al, 2006) is likely the reason for its high level of efficacy in treating libido, desire, and arousal disorders in various models as well as in different types of subjects.
Circadian Rhythm Effects
The effects and mechanisms of a-MSH and analogs on circadian rhythm are profound but have not been fully elucidated.
Aging rats exhibit a reversal of circadian rhythms with age. Alpha-MSH administration prevented this reversal (Yehuda and Carasso, 1983) indicating that a-MSH might be a potential chronotherapeutic agent in aging humans if applied at the right times to prevent the circadian rhythm dysfunction that occurs with age. The effects appeared to be mediated by multiple actions within the dopaminergic system (Yehuda and Carasso, 1983).
Yang et al found that a-MSH (or analogs such as MT-II) may have utility in re-entraining eating rhythms in a model of night-eating disorder, a type of circadian rhythm dysfunction:
"Our findings indicate that mPer2-/- mice do not have a glucocorticoid rhythm even though the corticosterone response to hypoglycemia, ACTH, and restraint stress is intact. In addition, the diurnal feeding rhythm is absent in mPer2-/- mice. On high-fat diet, they eat as much during the light period as they do during the dark period and develop significant obesity. The diurnal rhythm of neuroendocrine peptide alphaMSH, a major effector of appetite control, is disrupted in the hypothalamus of mPer2-/- mice even though the diurnal rhythm of ACTH, the alphaMSH precursor, is intact. Peripheral injection of alphaMSH, which has been shown to enter the brain, restored the feeding rhythm and induced weight loss in mPer2-/- mice. These findings emphasize the requirement of mPer2 in appetite control during the inactive period and the potential role of peripherally administered alphaMSH in restoring night-day eating pattern in individuals with circadian eating disorders such as night-eating syndrome, which is also associated with obesity. (2009)"
In the study, a-MSH was administered at the onset of light (with 12-hour dark/12-hour light rhythm). It was not specified how a-MSH analogs might potentially be used to re-entrain dysfunctional rhythms in humans, since rats have different activity/food-intake rhythms in response to entrained light/dark periods.
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