Agouti-related peptide

Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus.^[5] AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.^[6][7]

AGRP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1HYK, 1MR0
Identifiers
Aliases	AGRP, agouti related neuropeptide, AGRT, ART, ASIP2, AgRP
External IDs	OMIM: 602311 MGI: 892013 HomoloGene: 7184 GeneCards: AGRP
Gene location (Human) Chr. Chromosome 16 (human)^[1] Band 16q22.1 Start 67,482,571 bp^[1] End 67,483,547 bp^[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)^[2] Band 8|8 D3 Start 106,293,330 bp^[2] End 106,364,025 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left adrenal gland right adrenal gland corpus epididymis right lung caput epididymis upper lobe of left lung monocyte hypothalamus spleen nucleus accumbens Top expressed in median eminence arcuate nucleus morula spermatocyte entorhinal cortex ventromedial nucleus fossa mammillary body carotid body adrenal gland More reference expression data BioGPS n/a
Gene ontology Molecular function neuropeptide hormone activity signaling receptor binding Cellular component Golgi lumen extracellular region neuronal cell body Golgi apparatus extracellular space Biological process response to insulin adult feeding behavior neuropeptide signaling pathway regulation of feeding behavior positive regulation of feeding behavior circadian rhythm feeding behavior eating behavior maternal process involved in female pregnancy hormone-mediated signaling pathway long-day photoperiodism regulation of signaling receptor activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 181 11604 Ensembl ENSG00000159723 ENSMUSG00000005705 UniProt O00253 P56473 RefSeq (mRNA) NM_001138 NM_001271806 NM_007427 RefSeq (protein) NP_001129 NP_001258735 NP_031453 Location (UCSC) Chr 16: 67.48 – 67.48 Mb Chr 8: 106.29 – 106.36 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

AgRP is a paracrine signaling molecule made of 112 amino acids (the gene product of 132 amino acids is processed by removal of the N-terminal 20-residue signal peptide domain). It was independently identified by two teams in 1997 based on its sequence similarity with agouti signalling peptide (ASIP), a protein synthesized in the skin controlling coat colour.^[6][7] AgRP is approximately 25% identical to ASIP. The murine homologue of AgRP consists of 111 amino acids (precursor is 131 amino acids) and shares 81% amino acid identity with the human protein. Biochemical studies indicate AgRP to be very stable to thermal denaturation and acid degradation. Its secondary structure consists mainly of random coils and β-sheets^[8] that fold into an inhibitor cystine knot motif.^[9] AGRP maps to human chromosome 16q22 and Agrp to mouse chromosome 8D1-D2.

Function

Agouti-related protein is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with lower levels of expression in the testis, kidneys, and lungs. The appetite-stimulating effects of AgRP are inhibited by the hormone leptin and activated by the hormone ghrelin. Adipocytes secrete leptin in response to food intake. This hormone acts in the arcuate nucleus and inhibits the AgRP/NPY neuron from releasing orexigenic peptides.^[10] Ghrelin has receptors on NPY/AgRP neurons that stimulate the secretion of NPY and AgRP to increase appetite. AgRP is stored in intracellular secretory granules and is secreted via a regulated pathway.^[11] The transcriptional and secretory action of AgRP is regulated by inflammatory signals.^[12] Levels of AgRP are increased during periods of fasting. It has been found that AgRP stimulates the hypothalamic-pituitary-adrenocortical axis to release ACTH, cortisol and prolactin. It also enhances the ACTH response to IL-1-beta, suggesting it may play a role in the modulation of neuroendocrine response to inflammation.^[13] Conversely, AgRP-secreting neurons inhibit the release of TRH from the paraventricular nucleus (PVN), which may contribute to conservation of energy in starvation.^[14] This pathway is part of a feedback loop, since TRH-secreting neurons from PVN stimulate AgRP neurons.^[15]

Mechanism

AGRP has been demonstrated to be a competitive antagonist of melanocortin receptors, specifically MC3-R and MC4-R. The melanocortin receptors, MC3-R and MC4-R, are directly linked to metabolism and body weight control. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone) and antagonized by the agouti-related protein.^[16] Whereas α-MSH acts broadly on most members of the MCR family (with the exception of MC2-R), AGRP is highly specific for only MC3-R and MC4-R. This inverse agonism not only antagonizes the action of melanocortin agonists such as α-MSH but also further decreases the cAMP produced by the affected cells. The exact mechanism by which AgRP inhibits melanocortin-receptor signalling is not completely clear. It has been suggested that Agouti-related protein binds MSH receptors and acts as a competitive antagonist of ligand binding.^[17] Studies of Agouti protein in B16 melanoma cells supported this logic. The expression of AgRP in the adrenal gland is regulated by glucocorticoids. The protein blocks α-MSH-induced secretion of corticosterone.^[18]

History

Orthologs of AgRP, ASIP, MCIR, and MC4R have been found in mammalian, teleost fish, and avian genomes. This suggests that the agouti-melanocortin system evolved by gene duplication from individual ligand and receptor genes in the last 500 million years.^[16]

Role in obesity

AgRP induces obesity by chronic antagonism of the MC4-R.^[19] Overexpression of AgRP in transgenic mice (or intracerebroventricular injection) causes hyperphagia and obesity,^[20] whilst AgRP plasma levels have been found to be elevated in obese human males.^[21] Understanding the role AgRP plays in weight gain may assist in developing pharmaceutical models for treating obesity. AgRP mRNA levels have been found to be down regulated following an acute stressful event. Studies suggest that systems involved in the regulation of stress response and of energy balance are highly integrated. Loss or gain of AgRP function may result in inadequate adaptive behavioural responses to environmental events, such as stress, and have potential to contribute to the development of eating disorders. It has been shown that polymorphisms in the AgRP gene have been linked with anorexia nervosa^[22] as well as obesity. Some studies suggest that inadequate signalling of AgRP during stress may result in binge eating. Starvation-induced hypothalamic autophagy generates free fatty acids, which in turn regulate neuronal AgRP levels.^[23]

Agouti protein
Identifiers
Symbol	Agouti
Pfam	PF05039
Pfam clan	CL0083
InterPro	IPR007733
PROSITE	PDOC60024
SCOP2	1hyk / SCOPe / SUPFAM
OPM superfamily	112
OPM protein	1mr0
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Role in hunger circuitry

According to Mark L. Andermann and Bradford B. Lowell: "...AgRP neurons and the wiring diagram within which they operate can be viewed as the physical embodiment of the intervening variable, hunger."^[24] Stimulation of neurons expressing AgRP can induce robust feeding behavior in mice that will trigger: increased food consumption,^[25] increased willingness to work for food,^[26] and increased investigation of food odors.^[27]

Despite this, AgRP neurons are rapidly inhibited upon food presentation and the onset of eating.^[28] One mechanism which may account for this discrepancy is the fact that AgRP neurons signal with Neuropeptide Y in order to allow for sustained feeding behavior that outlasts the activation of the neurons.^[29]

AgRP neurons are also sensitive to satiety and hunger hormonal signals. One is an appetite stimulant, ghrelin which makes AgRP neurons more excitable through interactions with specialized ghrelin receptors.^[30] Another is a satiety signal, leptin, which modulates AgRP activity through inwardly rectifying potassium channels, which alter the excitability of the neurons.^[31] Leptin can also decrease the ability of AgRP neurons to carry out other physiological functions, such as triggering Long Term Potentiation of adjacent neurons.^[32]

Although AgRP neurons can drive many different phases of feeding behavior, separate AgRP neurons project to different areas of the brain, demonstrating a parallel organizational structure.^[33] This is evidenced by different projections of AgRP neurons to various areas of the brain driving different food related behaviors; for example, certain projections will promote increased food consumption, but not increased food odor investigation.^[27]

Human proteins containing this domain

AGRP; ASIP

See also

• Proopiomelanocortin
• Agouti (gene)

References

1. GRCh38: Ensembl release 89: ENSG00000159723 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000005705 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Bäckberg M, Madjid N, Ogren SO, Meister B (June 2004). "Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice". Brain Research. Molecular Brain Research. 125 (1–2): 129–39. doi:10.1016/j.molbrainres.2004.03.012. PMID 15193430.
6. Shutter JR, Graham M, Kinsey AC, Scully S, Lüthy R, Stark KL (March 1997). "Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice". Genes & Development. 11 (5): 593–602. doi:10.1101/gad.11.5.593. PMID 9119224.
7. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS (October 1997). "Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein". Science. 278 (5335): 135–8. doi:10.1126/science.278.5335.135. PMID 9311920.
8. Rosenfeld RD, Zeni L, Welcher AA, Narhi LO, Hale C, Marasco J, et al. (November 1998). "Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein". Biochemistry. 37 (46): 16041–52. doi:10.1021/bi981027m. PMID 9819197.
9. Jackson PJ, McNulty JC, Yang YK, Thompson DA, Chai B, Gantz I, et al. (June 2002). "Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity". Biochemistry. 41 (24): 7565–72. doi:10.1021/bi012000x. PMID 12056887.
10. Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, et al. (March 2007). "Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons". Cell Metabolism. 5 (3): 181–94. doi:10.1016/j.cmet.2007.02.004. PMID 17339026.
11. Creemers JW, Pritchard LE, Gyte A, Le Rouzic P, Meulemans S, Wardlaw SL, et al. (April 2006). "Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3". Endocrinology. 147 (4): 1621–31. doi:10.1210/en.2005-1373. PMID 16384863.
12. Scarlett JM, Zhu X, Enriori PJ, Bowe DD, Batra AK, Levasseur PR, et al. (October 2008). "Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretion by acute and chronic inflammation". Endocrinology. 149 (10): 4837–45. doi:10.1210/en.2007-1680. PMC 2582916. PMID 18583425.
13. Xiao E, Xia-Zhang L, Vulliémoz NR, Ferin M, Wardlaw SL (May 2003). "Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate". Endocrinology. 144 (5): 1736–41. doi:10.1210/en.2002-220013. PMID 12697678.
14. Nillni EA (April 2010). "Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs". Frontiers in Neuroendocrinology. 31 (2): 134–56. doi:10.1016/j.yfrne.2010.01.001. PMC 2849853. PMID 20074584.
15. Krashes MJ, Shah BP, Madara JC, Olson DP, Strochlic DE, Garfield AS, et al. (March 2014). "An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger". Nature. 507 (7491): 238–42. Bibcode:2014Natur.507..238K. doi:10.1038/nature12956. PMC 3955843. PMID 24487620.
16. Jackson PJ, Douglas NR, Chai B, Binkley J, Sidow A, Barsh GS, Millhauser GL (December 2006). "Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins". Chemistry & Biology. 13 (12): 1297–305. doi:10.1016/j.chembiol.2006.10.006. PMC 2907901. PMID 17185225.
17. Ollmann MM, Lamoreux ML, Wilson BD, Barsh GS (February 1998). "Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo". Genes & Development. 12 (3): 316–30. doi:10.1101/gad.12.3.316. PMC 316484. PMID 9450927.
18. Dhillo WS, Small CJ, Gardiner JV, Bewick GA, Whitworth EJ, Jethwa PH, et al. (January 2003). "Agouti-related protein has an inhibitory paracrine role in the rat adrenal gland". Biochemical and Biophysical Research Communications. 301 (1): 102–7. doi:10.1016/S0006-291X(02)02991-1. PMID 12535647.
19. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, et al. (January 1997). "Targeted disruption of the melanocortin-4 receptor results in obesity in mice". Cell. 88 (1): 131–41. doi:10.1016/S0092-8674(00)81865-6. PMID 9019399. S2CID 14528879.
20. Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL (November 1997). "Overexpression of Agrt leads to obesity in transgenic mice". Nature Genetics. 17 (3): 273–4. doi:10.1038/ng1197-273. PMID 9354787. S2CID 36127101.
21. Katsuki A, Sumida Y, Gabazza EC, Murashima S, Tanaka T, Furuta M, et al. (May 2001). "Plasma levels of agouti-related protein are increased in obese men". The Journal of Clinical Endocrinology and Metabolism. 86 (5): 1921–4. doi:10.1210/jcem.86.5.7458. PMID 11344185.
22. Vink T, Hinney A, van Elburg AA, van Goozen SH, Sandkuijl LA, Sinke RJ, et al. (May 2001). "Association between an agouti-related protein gene polymorphism and anorexia nervosa". Molecular Psychiatry. 6 (3): 325–8. doi:10.1038/sj.mp.4000854. PMID 11326303. S2CID 6755288.
23. Kaushik S, Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, et al. (August 2011). "Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance". Cell Metabolism. 14 (2): 173–83. doi:10.1016/j.cmet.2011.06.008. PMC 3148494. PMID 21803288.
24. Andermann ML, Lowell BB (August 2017). "Toward a Wiring Diagram Understanding of Appetite Control". Neuron. 95 (4): 757–778. doi:10.1016/j.neuron.2017.06.014. PMC 5657399. PMID 28817798.
25. Aponte Y, Atasoy D, Sternson SM (March 2011). "AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training". Nature Neuroscience. 14 (3): 351–5. doi:10.1038/nn.2739. PMC 3049940. PMID 21209617.
26. Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, et al. (April 2011). "Rapid, reversible activation of AgRP neurons drives feeding behavior in mice". The Journal of Clinical Investigation. 121 (4): 1424–8. doi:10.1172/JCI46229. PMC 3069789. PMID 21364278.
27. Horio N, Liberles SD (April 2021). "Hunger enhances food-odour attraction through a neuropeptide Y spotlight". Nature. 592 (7853): 262–266. Bibcode:2021Natur.592..262H. doi:10.1038/s41586-021-03299-4. PMC 8035273. PMID 33658716.
28. Chen Y, Lin YC, Kuo TW, Knight ZA (February 2015). "Sensory detection of food rapidly modulates arcuate feeding circuits". Cell. 160 (5): 829–841. doi:10.1016/j.cell.2015.01.033. PMC 4373539. PMID 25703096.
29. Chen Y, Essner RA, Kosar S, Miller OH, Lin YC, Mesgarzadeh S, Knight ZA (April 2019). Palmiter RD, Dulac C, Krashes MJ (eds.). "Sustained NPY signaling enables AgRP neurons to drive feeding". eLife. 8: e46348. doi:10.7554/eLife.46348. PMC 6513552. PMID 31033437.
30. Wang Q, Liu C, Uchida A, Chuang JC, Walker A, Liu T, et al. (February 2014). "Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin". Molecular Metabolism. 3 (1): 64–72. doi:10.1016/j.molmet.2013.10.001. PMC 3929914. PMID 24567905.
31. Baver SB, Hope K, Guyot S, Bjørbaek C, Kaczorowski C, O'Connell KM (April 2014). "Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus". The Journal of Neuroscience. 34 (16): 5486–96. doi:10.1523/JNEUROSCI.4861-12.2014. PMC 4298648. PMID 24741039.
32. Wang C, Zhou W, He Y, Yang T, Xu P, Yang Y, et al. (January 2021). "AgRP neurons trigger long-term potentiation and facilitate food seeking". Translational Psychiatry. 11 (1): 11. doi:10.1038/s41398-020-01161-1. PMC 7791100. PMID 33414382.
33. Betley JN, Cao ZF, Ritola KD, Sternson SM (December 2013). "Parallel, redundant circuit organization for homeostatic control of feeding behavior". Cell. 155 (6): 1337–50. doi:10.1016/j.cell.2013.11.002. PMC 3970718. PMID 24315102.

Further reading

• Dhillo WS, Gardiner JV, Castle L, Bewick GA, Smith KL, Meeran K, et al. (December 2005). "Agouti related protein (AgRP) is upregulated in Cushing's syndrome". Experimental and Clinical Endocrinology & Diabetes. 113 (10): 602–6. doi:10.1055/s-2005-872895. hdl:10044/1/270. PMID 16320160.
• Dinulescu DM, Cone RD (March 2000). "Agouti and agouti-related protein: analogies and contrasts". The Journal of Biological Chemistry. 275 (10): 6695–8. doi:10.1074/jbc.275.10.6695. PMID 10702221.
• Scarlett JM, Zhu X, Enriori PJ, Bowe DD, Batra AK, Levasseur PR, et al. (October 2008). "Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretion by acute and chronic inflammation". Endocrinology. 149 (10): 4837–45. doi:10.1210/en.2007-1680. PMC 2582916. PMID 18583425.
• Creemers JW, Pritchard LE, Gyte A, Le Rouzic P, Meulemans S, Wardlaw SL, et al. (April 2006). "Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3". Endocrinology. 147 (4): 1621–31. doi:10.1210/en.2005-1373. PMID 16384863.
• Katsuki A, Sumida Y, Gabazza EC, Murashima S, Tanaka T, Furuta M, et al. (May 2001). "Plasma levels of agouti-related protein are increased in obese men". The Journal of Clinical Endocrinology and Metabolism. 86 (5): 1921–4. doi:10.1210/jcem.86.5.7458. PMID 11344185.
• Kas MJ, Bruijnzeel AW, Haanstra JR, Wiegant VM, Adan RA (August 2005). "Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event". Journal of Molecular Endocrinology. 35 (1): 159–64. doi:10.1677/jme.1.01819. PMID 16087729.
• Jackson PJ, Yu B, Hunrichs B, Thompson DA, Chai B, Gantz I, Millhauser GL (October 2005). "Chimeras of the agouti-related protein: insights into agonist and antagonist selectivity of melanocortin receptors". Peptides. 26 (10): 1978–87. doi:10.1016/j.peptides.2004.12.036. PMID 16009463. S2CID 45039327.
• Bäckberg M, Madjid N, Ogren SO, Meister B (June 2004). "Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice". Brain Research. Molecular Brain Research. 125 (1–2): 129–39. doi:10.1016/j.molbrainres.2004.03.012. PMID 15193430.

External links

• agouti-related+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Agouti domain^{[permanent dead link]} in PROSITE
• Human AGRP genome location and AGRP gene details page in the UCSC Genome Browser.