The general function of MSH is the regulation of epidermal pigmentation. Activation of MC-1 receptors preferentially found in melanocytes and melanoma cells affects the distribution of melanin. The functional significance of this action centers on protective color changes in lower vertebrates - amphibians, reptiles and fishes. These species are able to change the number and size of the secretory granula of their epidermal melanocytes to adapt their body color to the background. MSH has also been identified in the skin of mammals (including humans). However, the involvement of MSH in pigmentation of the skin in higher vertebrates has not been demonstrated, although some evidence indicates that MSH in higher vertebrates, including humans, may affect hair color (rodents) and skin pigmentation. An example of a feasible relationship is given by the inverse correlation between susceptibility to sunburn, photo-ageing and skin cancer and the ability of an individual to tan after sun exposure. Healey and coworkers (2000) provided evidence of an association between the degree of tanning after repeated sun exposure and the number of variant MC1R alleles in individuals from Ireland and the UK. They suggest that MC1R gene status determines sun sensitivity.
In higher vertebrates, MSH is involved in a variety of additional functions. Intraventricular administration of a-MSH causes a stereotypic behavior in rats. MSH, ACTH and some of their derivates enhance aggression and influence learning and memory.
Dopamine (DA) is one of the most important transmitters, regulating MSH secretion from melanotrophs. Dopamine, acting via D2 receptors, has an inhibitory influence upon MSH secretion. Thus, lesions which destroy the DAergic fibers running to the intermediate lobe cause a rise in circulating a-MSH. Conversely, treatment with dopamine agonists can induce inhibition of a-MSH release.
Melanocortins participate in the regulation of multiple physiological functions. They are involved in grooming behavior, food intake and thermoregulation processes and can also modulate the response of the immune system in inflammatory states.
Animals have developed highly adaptive and redundant mechanisms to maintain energy balance by matching caloric intake to caloric expenditure. A role for a-MSH in the regulation of energy homeostasis is suggested by several lines of evidence. Regulation of signaling by melanocortin 3 and melanocortin 4 receptors in the CNS are controlled via neuronal cell bodies in the arcuate nucleus that produce a-MSH. Increased melanocortin signaling via pharmacological or genetic means in the CNS causes potent reductions in food intake and weight loss, whereas decreased melanocortin signaling results in increased food intake and weight gain. Injection of a-MSH into the lateral ventricle of rodents leads to suppression of food intake in a dose-dependent manner. In contrast, intraventricular (icv) administration of the melanocortin agonist MTII inhibits food intake in fasted mice. Moreover, the icv injection of a pharmacological antagonist of a-MSH (SHU9119) at sites containing MC-4 receptors results in increased feeding, supporting a role for endogenous melanocortins in appetite regulation. Alpha-MSH does not antagonize the appetite-stimulating effect of NPY after i.c.v. injection, although the melanocortin agonist MTII appears to suppress NPY-induced feeding. The idea that the melanocortin receptor system may be particularly important in modulating food intake is strengthened by the fact that transgenic mice, which lack MC-4 receptors, are massively overweight. Null mutations of the MC-4 receptor are associated with hyperphagia, obesity, hyperinsulinemia and hyperglycemia (Huszar et al. 1997).
In contrast to MC4-R knockout mice, MC3-R knockouts exhibit an exclusively metabolic syndrome. Homozygous MCR3-R -/- mice are not significantly overweight, but they exhibit an approximately 50-60% increase in fat mass and also exhibit an unusual increase in respiratory quotient when transferred onto high-fat diet, suggesting a reduced ratio of fat/carbohydrate oxidation. Furthermore, these knockout mice also exhibit an approximately 50% reduction in locomotor behavior, indicating reduced energy expenditure. Additionally, MSH seems to play an important role during early neurogenesis and exhibits a peak around parturition. The latter has been interpreted to mean that MSH plays a signaling role in the initiation of parturition.
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