Agouti related peptide

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Agouti-related peptide/Agouti-related protein (AgRP) is a neuropeptide produced by a subpopulation of neurones in the ventromedial part of the arcuate nucleus in the mammalian hypothalamus. The same neurons also produce neuropeptide Y (NPY). AgRP and NPY are both potent simulators of appetite when injected centrally (i.e. directly into the brain), and they decrease metabolism and energy expenditure. AgRP is also expressed in the adrenal gland and (at low levels) in several other peripheral tissues, including the testis, kidneys and lungs.

AgRP acts as an inverse agonist at melanocortin 3 and 4 (MC3 and MC4) receptors in the brain, thus it opposes the actions of the satiety-inducing neuropeptide alpha-melanocyte stimulating hormone, which is produced by neurones mainly in the dorsomedial part of the acrcuate nucleus. One of the major sites at which AgRP acts is in the paraventricular nucleus, which is directly innervated by the NPY/AgRP neurons, and where MC4 receptors are expressed on several neuronal populations, including on magnocellular oxytocin neurones and on presympathetic neurones. The NPY/AgRP neurones are directly activated in response to ghrelin, a hormone released from the empty stomach that is a potent stimulator of hunger. Conversely, they are inhibited by leptin, a hormone secreted by adipocytes in proportion to total body fat mass.[1][2]

The NPY/AgRP neurones use GABA as a conventional neurotransmitter. Transgenic mice engineered to be deficient from birth in either NPY or AgRP or both maintain a relatively normal body weight. However,if these neurones are selectively lesioned in adult mice, then the mice stop eating. Accordingly the neurons that make AgRP and NPY seem to be much more important for the regulation of appetite than these two neuropeptides, leading to the suggestion that it is their interaction with other neurones via GABA release that is critical. [3][4][5]

Structure

AgRP (in humans) is a peptide that consists of 132 amino acids, and was named because of its sequence similarity with Agouti signalling peptide (ASIP), a protein synthesised in skin that controls coat colour.[6][7] The presence of a 'disulfide through disulfide knot' structurally defines AgRP as a knottin. AgRP is approximately 25% identical to ASIP. Murine AgRP has 131 amino acids and shares 81% amino acid identity with the human protein. [8] The AgRP gene is located on human chromosome 16q22 and mouse chromosome 8D1-D2.

References

  1. Dinulescu DM, Cone RD (2000). "Agouti and agouti-related protein: analogies and contrasts". J Biol Chem 275: 6695–8. PMID 10702221.
  2. Belgardt BF et al. (2009) Hormone and glucose signalling in POMC and AgRP neuronsJ Physiol 587:5305-14 PMID 19770186
  3. Kaelin CB et al.(2008) New ligands for melanocortin receptors Int J Obes 32 Suppl 7:S19-27 PMID 19136986
  4. Coll AP, Tung LYC( 2009) Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis Mol Cell Endocrinol 300:147-51 PMID 18840502
  5. Flier JS (2006) AgRP in energy balance: Will the real AgRP please stand up? Cell Metab 3:83-5 PMID 16459309
  6. Shutter JR et al. (1997). "Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice". Genes & Development 11: 593–602. PMID 9119224.
  7. Ollmann MM et al. (1997). "Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein". Science 278: 135–8. PMID 9311920.
  8. Rosenfeld RD et al. (1998). "Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein". Biochemistry 37: 16041–52. PMID 9819197.