AgRP
Agouti is a 131 amino acid peptide secreted by dermal papilla cells during the hair growth cycle where it antagonizes the binding of alpha-MSH to the MC1 (melanocortin-1) receptor in the melanocyte. Agouti stimulates production of the red/yellow pigment pheomelanin by the follicular melanocyte while inhibiting production of the black/brown pigment eumelanin. Development. 1995 Oct;121(10):3223-32. While alpha MSH tends to darken the skin, Agouti lightens pigmentation.
Mice with over expression of Agouti due to a naturally occurring mutation of Agouti stimulating protein (Ay mice) develop a yellow coating due to the increased actions of Agouti on MC1r receptors in the skin. Simultaneous antagonism of the MC4r receptors in the brain in these mice by Agouti-stimulating-protein results in hyperphagia, obesity, type 2 diabetes, hyperleptinaemia, increased linear growth, and infertility. Administration of a melanocortin agonist does not reverse this obese phenotype, Int J Obes Relat Metab Disord. 1998 Jul;22(7):678-83. while an MC4r agonist inhibits feeding. MC4r knock out mice behave similar to agouti lethal yellow mice in exhibiting hyperphagia, obesity and hyperinsulinaemia without the yellow coat. Cell. 1997 Jan 10;88(1):131-41. corroborating the melanocortin antagonism by Agouti in the brain.
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Agouti related peptide (AgRP) is a 132 aminoacid peptide with 25% homology to agouti. Biochem Biophys Res Commun. 1997 Aug 28;237(3):629-31. AgRP is produced in the arcuate nucleus of the hypothalamus and is shorter than the agouti peptide. AgRP mRNA is abundantly co-localised with NPY. AgRP is co-secreted with Neuropeptide Y and is an endogenous antagonist of the hypothalamic MC4 receptor. Thus while α-MSH is an agonist of the melanocortin system, AgRP acts as an endogenous antagonist in the melanocortin system. AgRP increases food intake and decreases energy expenditure by antagonism of the MC-3 and MC-4 receptors while increasing the orexigenic NPY signalling. Int J Obes Relat Metab Disord. 2001 Dec;25 Suppl 5:S56-62 The NPY/AgRP system can thus sense and respond (via leptin and insulin changes) to various peripheral hormonal and nutrient signals relevant to the regulation of short and long term energy balance .
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Injection of AgRP into third ventricle of rats inhibits the anorexigenic and weight-gain inhibiting action of alpha MSH. Over expression of AgRP results in obesity in mice. Recent Prog Horm Res. 2001;56:359-75 without the yellow coat colour as AgRP has low affinity for MC1 receptors. Science. 1997 Oct 3;278(5335):135-8. Obese men have higher plasma AgRP level than non-obese men, with the AgRP levels correlating well with visceral fat and serum alpha-MSH levels. J. Clin. Endocrinol. Metab., May 2001; 86: 1921 - 1924 NPY/AgRP gene expression is up-regulated during periods of negative energy balance, facilitating increased energy intake. Leptin and Insulin inhibit the NPY/AgRP neurons, while a lack of this inhibition results in activation of the NPY/AgRP system resulting in positive energy balance through hyperphagia.
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AgRP is not as potent as NPY in its acute effects on feeding stimulation, but its effects on feeding are as prolonged as 6 days Am J Physiol Regul Integr Comp Physiol. 2000 Jul;279(1):R47-52 in contrast to the 24 hour action of NPY, despite degradation over a few hours. This is probably due to the fact that AgRP exerts its action on the MC4R receptor through a cell surface molecule named syndecan-3, which acts as a co-receptor. Infact over expression of syndecan-1, a related molecule results in obesity due to increased facilitation of AgRP signalling with melanocortin antagonism. Cell. 2001 Jul 13;106(1):105-16. Another explanation is probably offered by the fact that the immediate actions of AgRP are blocked by opioid receptor antagonists but not the longer term effects, Am J Physiol Regul Integr Comp Physiol. 2001 Mar;280(3):R814-21 suggesting that different pathways may sustain the action of AgRP. Note that both AgRP and alpha MSH produce opposite effects on feeding, both mediated via the MC4r receptor in the paraventricular nucleus of the hypothalamus. This melanocortin system is thus unique in neuroendocrinology in having both agonistic and antagonistic endogenous ligands which regulate stimulation and inhibition of food intake depending on the state of energy balance.
Fasting induces an increase in Agrt (agouti related transcript) with a reduction in peptide levels. Nat Neurosci. 1998 Aug;1(4):271-2
Fasting induces an increase in Agrt (agouti related transcript) with a reduction in peptide levels. Nat Neurosci. 1998 Aug;1(4):271-2