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Gene Review

AGRP  -  agouti related neuropeptide

Homo sapiens

Synonyms: AGRT, ART, ASIP2, Agouti-related protein, Agrt
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Disease relevance of AGRP


Psychiatry related information on AGRP


High impact information on AGRP

  • Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake [9].
  • Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp [9].
  • Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation [10].
  • This new regulatory mechanism was likewise detectable in a cell line derived from murine hypothalamic neurons endogenously expressing MC4R, pointing to the physiological relevance of Agrp-promoted receptor endocytosis [11].
  • Sustained exposure of human embryonic kidney 293 cells to Agrp induced endocytosis of the MC3R or the MC4R [11].

Biological context of AGRP

  • The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs [12].
  • Agouti and agouti-related protein (AGRP) are natural antagonists of melanocortin receptors and participate in regulation of skin/fur pigmentation, body weight, and adiposity [13].
  • Although a complete deletion of the AGRP gene does not produce any significant metabolic phenotypes, reduction in AGRP expression by RNA interference is associated with increased metabolic rate along with reduced weight gain [3].
  • These findings suggest that serum MCH and possibly AGRP levels could serve as useful peripheral markers of changes in energy homeostasis and thus merit additional investigation [14].
  • Novel inhibitors of the AGRP/MC4 binding based on (piperazinylethyl)piperazines were prepared, and their structure-activity relationship was established [15].

Anatomical context of AGRP

  • The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits potent orexigenic activity [16].
  • Infundibular nucleus (including median eminence) NPY ICC staining or mRNA expression, and AGRP ICC staining, increased with premorbid illness duration [4].
  • Animal studies have demonstrated the importance of orexigenic NPY and agouti-related protein (AGRP) hypothalamic neurons, which are inhibited by the adipocyte hormone leptin, in the regulation of body weight and neuroendocrine secretion [4].
  • NPY-, AGRP-, and alphaMSH-containing axons densely innervated the hypothalamic paraventricular nucleus and were found in close juxtaposition to TRH-synthesizing cell bodies and dendrites [17].
  • The demonstration that AGRP is an endogenous antagonist with respect to these receptors is a unique mechanism within the central nervous system, and has important implications in the control of feeding [18].

Associations of AGRP with chemical compounds

  • Substitutions of the extracytoplasmic NH2 terminus and the first extracytoplasmic loop (exoloop) of the MC4R with homologous domains of the MC1R had no effect on AGRP (87-132) binding affinity or inhibitory activity (the ability to inhibit melanocortin-stimulated cAMP generation) [6].
  • This hypothesis is tested here with NMR structure and activity studies of a 34-residue AGRP analogue designed to contain only the cystine knot domain [16].
  • Notably, mutation of TM3 residue D126 to alanine decreased the binding affinity of AGRP (87-132), a C-terminal derivative of the endogenous melanocortin antagonist, 8-fold, and simultaneous mutations D122A/D126A completely abolished AGRP (87-132) binding [19].
  • There was a significant stimulatory effect of 20 microg AGRP on cortisol release over time (P < 0.001) [20].
  • In the models of the ASIP fragment complexed with both receptors, the core ligand tripeptide, Arg-Phe-Phe, positioned between TMHs 3 and 6, is shifted toward TMHs 2 and 7 relative to its position in the AGRP-hMC4R model, while the N-terminal loop and two central disulfides of the antagonists interact with EL2 of the receptors [21].

Physical interactions of AGRP

  • Although previous studies have shown that AGRP binds three of the five known subtypes of melanocortin receptor, the receptor domains participating in binding and the molecular interactions involved are presently unknown [6].

Regulatory relationships of AGRP


Other interactions of AGRP


Analytical, diagnostic and therapeutic context of AGRP

  • Two polymorphisms were detected in the AGRP -encoding sequence (a silent mutation in exon 1 and Ala67Thr in exon 2), with similar frequencies in the obese and control groups [2].
  • We first assessed correlations of serum MCH, AGRP, and alpha-MSH with anthropometric, dietary, and hormonal variables in a cross-sectional study of 108 healthy humans [14].
  • Mobility shifts observed using SDS-PAGE under reducing and nonreducing conditions for bacterially expressed and mammalian expressed AGRP were identical, an indication of a similar disulfide structure [18].
  • The resulting proteins were characterized by peptide mapping, sequence analysis, and mass spectrometry, showing that AGRP contained a highly reducible disulfide bond, C85-C109, followed by less reactive ones, C90-C97, C74-C88, C67-C82, and C81-C99, respectively [24].
  • To study the possibility of disturbances in melanocortin receptor-related peptides in eating disorders, plasma AGRP, alpha-MSH, and leptin levels were measured in 18 female patients with anorexia nervosa (AN) (age, 23.5+/-7.1yr; body mass index (BMI) 14.5+/-1.8kg/m(2)) and 17 age-matched female controls (age, 25.8+/-3.9yr; BMI 20.2+/-1.6kg/m(2)) [25].


  1. Association between an agouti-related protein gene polymorphism and anorexia nervosa. Vink, T., Hinney, A., van Elburg, A.A., van Goozen, S.H., Sandkuijl, L.A., Sinke, R.J., Herpertz-Dahlmann, B.M., Hebebrand, J., Remschmidt, H., van Engeland, H., Adan, R.A. Mol. Psychiatry (2001) [Pubmed]
  2. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. Dubern, B., Clément, K., Pelloux, V., Froguel, P., Girardet, J.P., Guy-Grand, B., Tounian, P. J. Pediatr. (2001) [Pubmed]
  3. The physiological function of the agouti-related peptide gene: the control of weight and metabolic rate. Mizuno, T.M., Makimura, H., Mobbs, C.V. Ann. Med. (2003) [Pubmed]
  4. Hypothalamic NPY and agouti-related protein are increased in human illness but not in Prader-Willi syndrome and other obese subjects. Goldstone, A.P., Unmehopa, U.A., Bloom, S.R., Swaab, D.F. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  5. Two ethnic-specific polymorphisms in the human Agouti-related protein gene are associated with macronutrient intake. Loos, R.J., Rankinen, T., Rice, T., Rao, D.C., Leon, A.S., Skinner, J.S., Bouchard, C., Argyropoulos, G. Am. J. Clin. Nutr. (2005) [Pubmed]
  6. Contribution of melanocortin receptor exoloops to Agouti-related protein binding. Yang, Y.K., Dickinson, C.J., Zeng, Q., Li, J.Y., Thompson, D.A., Gantz, I. J. Biol. Chem. (1999) [Pubmed]
  7. Neuropeptides in hypothalamic neuronal disorders. Swaab, D.F. Int. Rev. Cytol. (2004) [Pubmed]
  8. Regulation of leptin receptor, POMC and AGRP gene expression by photoperiod and food deprivation in the hypothalamic arcuate nucleus of the male Siberian hamster (Phodopus sungorus). Mercer, J.G., Moar, K.M., Ross, A.W., Morgan, P.J. Appetite. (2000) [Pubmed]
  9. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Kitamura, T., Feng, Y., Ido Kitamura, Y., Chua, S.C., Xu, A.W., Barsh, G.S., Rossetti, L., Accili, D. Nat. Med. (2006) [Pubmed]
  10. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., Barsh, G.S. Science (1997) [Pubmed]
  11. The Natural Inverse Agonist Agouti-related Protein Induces Arrestin-mediated Endocytosis of Melanocortin-3 and -4 Receptors. Breit, A., Wolff, K., Kalwa, H., Jarry, H., B??ch, T., Gudermann, T. J. Biol. Chem. (2006) [Pubmed]
  12. The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs. Klovins, J., Haitina, T., Fridmanis, D., Kilianova, Z., Kapa, I., Fredriksson, R., Gallo-Payet, N., Schiöth, H.B. Mol. Biol. Evol. (2004) [Pubmed]
  13. The role of melanocortin peptides and receptors in regulation of energy balance. Zimanyi, I.A., Pelleymounter, M.A. Curr. Pharm. Des. (2003) [Pubmed]
  14. Circulating melanin-concentrating hormone, agouti-related protein, and alpha-melanocyte-stimulating hormone levels in relation to body composition: alterations in response to food deprivation and recombinant human leptin administration. Gavrila, A., Chan, J.L., Miller, L.C., Heist, K., Yiannakouris, N., Mantzoros, C.S. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  15. Structure-activity relationship of (1-aryl-2-piperazinylethyl)piperazines: antagonists for the AGRP/melanocortin receptor binding. Arasasingham, P.N., Fotsch, C., Ouyang, X., Norman, M.H., Kelly, M.G., Stark, K.L., Karbon, B., Hale, C., Baumgartner, J.W., Zambrano, M., Cheetham, J., Tamayo, N.A. J. Med. Chem. (2003) [Pubmed]
  16. Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity. Jackson, P.J., McNulty, J.C., Yang, Y.K., Thompson, D.A., Chai, B., Gantz, I., Barsh, G.S., Millhauser, G.L. Biochemistry (2002) [Pubmed]
  17. Hypophysiotropic thyrotropin-releasing hormone-synthesizing neurons in the human hypothalamus are innervated by neuropeptide Y, agouti-related protein, and alpha-melanocyte-stimulating hormone. Mihály, E., Fekete, C., Tatro, J.B., Liposits, Z., Stopa, E.G., Lechan, R.M. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  18. Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein. Rosenfeld, R.D., Zeni, L., Welcher, A.A., Narhi, L.O., Hale, C., Marasco, J., Delaney, J., Gleason, T., Philo, J.S., Katta, V., Hui, J., Baumgartner, J., Graham, M., Stark, K.L., Karbon, W. Biochemistry (1998) [Pubmed]
  19. Molecular determinants of ligand binding to the human melanocortin-4 receptor. Yang, Y.K., Fong, T.M., Dickinson, C.J., Mao, C., Li, J.Y., Tota, M.R., Mosley, R., Van Der Ploeg, L.H., Gantz, I. Biochemistry (2000) [Pubmed]
  20. Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate. Xiao, E., Xia-Zhang, L., Vulliémoz, N.R., Ferin, M., Wardlaw, S.L. Endocrinology (2003) [Pubmed]
  21. Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors. Chai, B.X., Pogozheva, I.D., Lai, Y.M., Li, J.Y., Neubig, R.R., Mosberg, H.I., Gantz, I. Biochemistry (2005) [Pubmed]
  22. High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein. McNulty, J.C., Thompson, D.A., Bolin, K.A., Wilken, J., Barsh, G.S., Millhauser, G.L. Biochemistry (2001) [Pubmed]
  23. Leptin sensitive neurons in the hypothalamus. Baskin, D.G., Hahn, T.M., Schwartz, M.W. Horm. Metab. Res. (1999) [Pubmed]
  24. Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation. Bures, E.J., Hui, J.O., Young, Y., Chow, D.T., Katta, V., Rohde, M.F., Zeni, L., Rosenfeld, R.D., Stark, K.L., Haniu, M. Biochemistry (1998) [Pubmed]
  25. Plasma agouti-related protein levels in women with anorexia nervosa. Moriya, J., Takimoto, Y., Yoshiuchi, K., Shimosawa, T., Akabayashi, A. Psychoneuroendocrinology (2006) [Pubmed]
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