α MSH is a product of POMC gene, and inhibits food intake through the melanocortin system. The connection between obesity and the melanocortin pathway was brought to light by identification of very young patients with POMC gene mutations and resultant decreased α MSH with hyperphagia and obesity starting in the first month of life. Nat Genet. 1998 Jun;19(2):155-7. Increasing evidence suggests that peripheral signals from adipose tissue and the gut may talk to the satiety centres in the brain through this pathway.
POMC is synthesised in the arcuate nucleus of the hypothalamus from where the neurons project to the PVN. Nature. 2000 Apr 6;404(6778):661-71 α MSH which is produced from POMC, acts on the hypothalamus via the MC4 receptor. Central administration of α MSH or its synthetic analogue as Melanotan II Brain Res. 2003 Jul 11;977(2):221-30. produces significant reduction in food intake with loss of body weight. Melanotan II also prevents NPY induced feeding in rats. Nature. 1997 Jan 9;385(6612):165-8. The anorexigenic and weight-gain inhibiting action of α MSH can be prevented by AgRP injection into third ventricle of rats. Thus α MSH and AgRP produce opposing effects on feeding, both mediated via the MC4r receptor in the paraventricular nucleus of the hypothalamus. POMC is also synthesised in the caudal brainstem although its role here remains to be clarified. AgRP immunoreactivity is low or absent in the brainstem, and it seems unlikely that hypothalamic AgRP regulates the melanocortin tone in the brainstem unlike in the hypothalamic milieu.
POMC is co-expressed with another anorexigenic peptide- CART (cocaine and amphetamine regulated transcript) in the arcuate nucleus. This combination is opposed by AgRP and NPY both of which are also co-secreted in a different set of neurones in the arcuate nucleus itself. Nature. 2000 Apr 6;404(6778):661-71 Other Neuropeptides as MCH (Melanocyte Concentrating Hormone) and Orexins A and B expressed in the lateral hypothalamus may mediate their actions through the POMC and AgRP neurones. Nature. 2000 Apr 6;404(6778):661-71 . Serotonin receptors are present on POMC neurones and implicate the melanocortin pathway in the therapeutic potential of serotonergic agonists (dexfenfluramine) in obesity, which have been shown to increase POMC activity.Science. 2002 Jul 26;297(5581):609-11.
POMC is synthesised in the arcuate nucleus of the hypothalamus from where the neurons project to the PVN. Nature. 2000 Apr 6;404(6778):661-71 α MSH which is produced from POMC, acts on the hypothalamus via the MC4 receptor. Central administration of α MSH or its synthetic analogue as Melanotan II Brain Res. 2003 Jul 11;977(2):221-30. produces significant reduction in food intake with loss of body weight. Melanotan II also prevents NPY induced feeding in rats. Nature. 1997 Jan 9;385(6612):165-8. The anorexigenic and weight-gain inhibiting action of α MSH can be prevented by AgRP injection into third ventricle of rats. Thus α MSH and AgRP produce opposing effects on feeding, both mediated via the MC4r receptor in the paraventricular nucleus of the hypothalamus. POMC is also synthesised in the caudal brainstem although its role here remains to be clarified. AgRP immunoreactivity is low or absent in the brainstem, and it seems unlikely that hypothalamic AgRP regulates the melanocortin tone in the brainstem unlike in the hypothalamic milieu.
POMC is co-expressed with another anorexigenic peptide- CART (cocaine and amphetamine regulated transcript) in the arcuate nucleus. This combination is opposed by AgRP and NPY both of which are also co-secreted in a different set of neurones in the arcuate nucleus itself. Nature. 2000 Apr 6;404(6778):661-71 Other Neuropeptides as MCH (Melanocyte Concentrating Hormone) and Orexins A and B expressed in the lateral hypothalamus may mediate their actions through the POMC and AgRP neurones. Nature. 2000 Apr 6;404(6778):661-71 . Serotonin receptors are present on POMC neurones and implicate the melanocortin pathway in the therapeutic potential of serotonergic agonists (dexfenfluramine) in obesity, which have been shown to increase POMC activity.Science. 2002 Jul 26;297(5581):609-11.
Melanocortin Receptors
Five different types of Melanocortin receptors have been described. MC1 receptor is involved in pigmentation of the skin, MC2 in mediating the actions of ACTH and thus regulation of steroid synthesis and secretion, and MC5 in inflammatory responses. MC3 and MC4 are the predominant receptors involved in mediating energy balance. MC4 receptors are mainly expressed in the paraventricular nucleus (PVN) of the hypothalamus, although they are also detectable in the nucleus accumbens and dorsal motor nucleus of the vagus. J Neurosci. 2003 Aug 6;23(18):7143-54. Deletion of the MC4 receptor in mice cause hyperphagia and obesity, while ICV administration of MC4r agonist to fasted mice causes inhibition of food intake. Recent Prog Horm Res. 2001;56:359-75MC4r agonist-induced suppression of food intake can be prevented by concomitant treatment with MC4r antagonist. |
MC3 receptors are also expressed in the POMC/CART and AgRP/NPY neurons in the arcuate nucleus. Targeted deletion of MC3r gene in transgenic mice results in higher susceptibility to diet induced obesity resulting in a late-onset-obesity phenotype with intact regulation of appetite and metabolism. Eur J Pharmacol. 2002 Apr 12;440(2-3):189-97. But interestingly, deletion of MC3 receptors in rats results in no change in body weight, although adiposity increases with concomitant decrease in lean body mass Endocrinology. 2000 Sep;141(9):3518-21. Thus, while MC3 receptor manipulation may not produce weight loss, agonism at this receptor may facilitate a beneficial alteration in body composition Int J Impot Res. 2000 Oct;12 Suppl 4:S74-9 emphasizing the need to achieve selective targeting of these receptors in the quest for effective obesity treatment. Twice daily treatment with intranasal MC4 receptor selective agonist (desacetyl-α MSH), as well as non-selective treatment with MSH/ACTH(4-10) was undertaken for 6 weeks in 36 normal weight humans. J Clin Endocrinol Metab. 2001 Mar;86(3):1144-8 Intranasal administration was used in this study to effect direct delivery to the CNS. Surprisingly, while the non-selective agonist produced reduction in body weight, the selective agonist failed to demonstrate significant reduction in adiposity. Clearly, other factors influencing the effect of selective receptor agonism need to be elucidated. |
Peripheral signals from adipose tissue as Leptin interact with the central quartet (NPY/AgRP and POMC/CART) influencing energy intake depending on the fed state of the animal. Leptin receptors are expressed in these central neurones with up to 40% of POMC neurones expressing mRNA for the long form of Leptin receptor. Endocrinology. 1997 Oct;138(10):4489-92. Central administration of leptin stimulates POMC gene expression in fasting animals. Diabetes.1997 Dec;46(12):2119-23. Leptin-deficient mice have higher expression of AgRP and decreased POMC expression, a situation that can be normalised by Leptin administration. Diabetes. 1998 Feb;47(2):294-7. Leptin seems to produce satiety through stimulation of POMC/CART neurones, and inhibition of AgRP/NPY neurones, with reversal of effects during food deprivation to stimulate appetite. Effect of ICV leptin on food intake is blunted if MC3R / MC4R antagonists are co-administered with leptin. Agents acting directly on POMC receptors have the potential to bypass the postulated leptin resistance in obese patients offering a potential therapeutic role for POMC agonism. Gut hormones as Ghrelin (orexigenic) and Peptide YY (anorexigenic) decrease Ann N Y Acad Sci. 2003 Jun;994:175-86. and increase Nature. 2002 Aug 8;418(6898):650-4. the POMC neuronal activity respectively, suggesting the role of the melanocortin pathway in transmitting gut signals regarding satiety to the brain. Ghrelin increases c fos activity in the NPY/AgRP neurons but not in the POMC neurons Neurosci Lett. 2002 May 31;325(1):47-51. suggesting that the hyperpolarisation of POMC neurons induced by Ghrelin might be mediated through GABA release by NPY/AgRP neuron depolarisation. Neuron. 2003 Feb 20;37(4):649-61. While leptin might transmit signals regarding energy balance over a long term, the gut hormones might mediate short term signalling due to rapid fluctuation with meals. |
Melanocortins and glucose homeostasis
The melanocortin system seems to have effects on glucose homeostasis independent of food intake. While α MSH administration increases plasma glucose, insulin and glucagon levels, Horm Metab Res. 1986 Sep;18(9):579-83. POMC deficiency results in predominantly defective glucagon mediated counter regulatory responses to hypoglycaemia Endocrinology. 2003 Dec;144(12):5194-202 although the hypocortisolaemia in these latter subjects could be confounding the picture. MC4R knock out mice Cell. 1997 Jan 10;88(1):131-41 as well as MC3R knock out mice Obes Res. 1999 Sep;7(5):506-14. show defects in glucose handling with marked hyperinsulinaemia, hyperphagia and diabetes mellitus. Studies on MC4R knock outs show that the dysregulation of insulin secretion seems to be an early onset phenomenon antedating the glucose or weight changes Endocrinology. 2000 Sep;141(9):3072-9 suggesting a primary influence of the melanocortin system on pancreatic islets. This influence may be sympathetic system-mediated as shown using phentolamine-blockade of the Melanotan II actions on ob/ob mice. Melanotan decreases insulin concentration in these ob/ob mice independent of blood glucose reduction. Endocrinology. 2000 Sep;141(9):3072-9 |
Melanocortins and Reproduction
α MSH produces erections in male rodents, Neurosci Biobehav Rev. 1999 Dec;23(8):1127-42. with stimulation of sexual receptivity in female rodents on central administration. Neuropeptides. 2000 Jun-Aug;34(3-4):211-5. α MSH has been shown to modulate gonadotropins in men J Endocrinol Invest.1997 Apr;20(4):207-10. and female rats. J Endocrinol. 1990 Jan;124(1):127-32. with the alpha MSH agonist Melanotan II producing erections in men. Urology. 2000 Oct 1;56(4):641-6. Although POMC deficient patients seem to have normal reproductive function, Nat Genet. 1998 Jun;19(2):155-7. MC4R knock out mice have impaired reproductive behaviour. Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11381-6 Up to 26 mutations of the human MC4 receptor have been identified. 3-4% of early onset obesity is associated with mutations in the MC4 receptor, J Clin Invest. 2000 Jul;106(2):271-9. and thus MC4r mutations are the most common monogenic determinants of obesity in humans. Loss of function mutations in the POMC gene have been described characterised by early onset obesity, red hair and adrenal insufficiency. Nature. 2000 Apr 6;404(6778):644-51. Pro-hormone convertase-I is the enzyme that cleaves POMC to produce α MSH. Mutations in the genes for pro-convertase I and carboxypeptidase E Nature. 2000 Apr 6;404(6778):661-71; J Clin Endocrinol Metab. 1999 Feb;84(2):819-20 can disrupt melanocortin signalling resulting in disturbed α MSH mediated actions and obesity in humans but not in rats. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10293-8 The contribution of polymorphisms in the MC4 receptor towards development of obesity remains to be elucidated. While agonism of central MC4 receptors remains an attractive option to treat obesity, side effects as unwarranted erections due to actions on peripheral MC4 receptors might necessitate further modifications of the approach. Compensatory AgRP increase could limit long term effectiveness of MC4 agonism, and countering AgRP might be a concomitant approach to pursue. Nasal Peptide YY is currently rapidly coming up as a clinically relevant therapeutic option, 86th Annual Meeting of The Endocrine Society (ENDO 2004), New Orleans, LA, June, 2004 with mediation of actions at least partly through the melanocortin pathway |