Пептид, связанный с агутией
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| Псевдонимы | Agrp , Aguti, связанный с нейропептидом, Agrt, Art, Asip2, Agrp | ||||||||||||||||||||||||||||||||||||||||||||||||||
| Внешние идентификаторы | Омим : 602311 ; MGI : 892013 ; Гомологен : 7184 ; Genecards : Agrp ; OMA : AGRP - ортологи | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Связанный с AGUTI белок ( AGRP ), также называемый пептидом, связанным с AGOUTI , представляет собой нейропептид, продуцируемый в мозге нейроном AGRP/NPY. Он синтезируется в нейропептидном Y (NPY)-содержащих клеточных телах, расположенных в вентомедиальной части дугообразного ядра в гипоталамусе. [ 5 ] AGRP совместно экспрессируется с NPY и ACTS для увеличения аппетита и снижения метаболизма и расходов на энергию. Это один из самых мощных и долговечных стимуляторов аппетита. У людей пептид, связанный с Aguti, кодируется AGRP геном . [ 6 ] [ 7 ]
Структура
[ редактировать ]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 отображает хромосому человека 16Q22 и AGRP с хромосомой мыши 8D1-D2.
Function
[edit]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
[edit]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
[edit]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
[edit]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 | |||
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| Identifiers | |||
| Symbol | Agouti | ||
| Pfam | PF05039 | ||
| Pfam clan | CL0083 | ||
| InterPro | IPR007733 | ||
| PROSITE | PDOC60024 | ||
| SCOP2 | 1hyk / SCOPe / SUPFAM | ||
| OPM superfamily | 112 | ||
| OPM protein | 1mr0 | ||
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Role in hunger circuitry
[edit]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
[edit]AGRP; ASIP
See also
[edit]References
[edit]- ^ Jump up to: a b c GRCh38: Ensembl release 89: ENSG00000159723 – Ensembl, May 2017
- ^ Jump up to: a b c GRCm38: Ensembl release 89: ENSMUSG00000005705 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ Jump up to: a b 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.
- ^ Jump up to: a b 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Jump up to: a b 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Jump up to: a b 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.
- ^ 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.
- ^ Чен Й., Эсснер Р.А., Косар С., Миллер О.Х., Лин Ю.К., Месгарзаде С., Найт Зай (апрель 2019). Palmiter RD, Dulac C, Krashes MJ (Eds.). «Устойчивая передача сигналов NPY позволяет AGRP -нейронам стимулировать кормление» . элиф . 8 : E46348. doi : 10.7554/elife.46348 . PMC 6513552 . PMID 31033437 .
- ^ Wang Q, Liu C, Uchida A, Chuang JC, Walker A, Liu T, et al. (Февраль 2014 г.). «Арвенные нейроны AGRP опосредуют орексигенные и глюкорегуляторные действия грелина» . Молекулярный метаболизм . 3 (1): 64–72. doi : 10.1016/j.molmet.2013.10.001 . PMC 3929914 . PMID 24567905 .
- ^ Baver SB, Hope K, Guyot S, Bjørbaek C, Kaczorowski C, O'Connell KM (апрель 2014 г.). «Лептин модулирует внутреннюю возбудимость нейронов AgRP/NPY в дугообразном ядре гипоталамуса» . Журнал нейробиологии . 34 (16): 5486–96. doi : 10.1523/jneurosci.4861-12.2014 . PMC 4298648 . PMID 24741039 .
- ^ Wang C, Zhou W, He Y, Yang T, Xu P, Yang Y, et al. (Январь 2021 г.). «Нейроны AGRP вызывают долгосрочное потенцирование и облегчают поиск пищи» . Переводная психиатрия . 11 (1): 11. doi : 10.1038/s41398-020-01161-1 . PMC 7791100 . PMID 33414382 .
- ^ Betley JN, Cao ZF, Ritola KD, Sternson SM (декабрь 2013 г.). «Параллельная, избыточная схема организации для гомеостатического контроля поведения кормления» . Клетка . 155 (6): 1337–50. doi : 10.1016/j.cell.2013.11.002 . PMC 3970718 . PMID 24315102 .
Дальнейшее чтение
[ редактировать ]- Dhillo WS, Gardiner JV, Castle L, Bewick GA, Smith KL, Meeran K, et al. (Декабрь 2005 г.). «Белок, связанный с агути (AGRP), активируется при синдроме Кушинга». Экспериментальная и клиническая эндокринология и диабет . 113 (10): 602–6. doi : 10.1055/s-2005-872895 . HDL : 10044/1/270 . PMID 16320160 .
- Dinuescu DM, Cone Rd (март 2000 г.). «Агути и агути-белок: аналогии и контрасты» . Журнал биологической химии . 275 (10): 6695–8. doi : 10.1074/jbc.275.10.6695 . PMID 10702221 .
- Скарлетт JM, Zhu X, Enriori PJ, Bowe DD, Batra AK, Levasseur PR, et al. (Октябрь 2008 г.). «Регуляция транскрипции белковой филово-килограммы и пептидов, связанного с Agouti, с помощью острого и хронического воспаления» . Эндокринология . 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. (Апрель 2006 г.). «Связанный с AGOUTI белок посттрансляционно расщепляется пропротеин-конвертазой 1 для генерации белка, связанного с AGOUTI (AGRP) 83-132: взаимодействие между AGRP83-132, и меланокортиновые рецепторы не могут зависеть от синдекана-3». Эндокринология . 147 (4): 1621–31. doi : 10.1210/en.2005-1373 . PMID 16384863 .
- Katsusuita A, Addry Y, Gabazza EC, Maraashimas S, Kiss T, Fruta M, et al. (2001). Полем Журнал клинической эндокринологии и метаболизма . 86 (5): 1921–4 doi : 10.1210/jcem.86.5.7458 . PMID 11344185 .
- Kas MJ, Bruijnzeel AW, Hanstra JR, Wegant VM, Adan RA (август 2005 г.). «Дифференциальная регуляция связанного с агутированным белком и нейропептидом Y в нейронах гипоталамуса после стресса » Журнал молекулярной эндокринологии 35 (1): 159–6 Doi : 10.1677/ jme.1.0 16087729PMID
- Джексон П.Дж., Ю. Б., Хунрихс Б., Томпсон Д.А., Чай Б., Ганц И., Милхаузер Г.Л. (октябрь 2005 г.). «Химеры белка, связанного с агутией: понимание селективности агонистов и антагонистов рецепторов меланокортина». Пептиды . 26 (10): 1978–87. doi : 10.1016/j.peptides.2004.12.036 . PMID 16009463 . S2CID 45039327 .
- Bäckberg M, Madjid N, Ogren SO, Meister B (июнь 2004 г.). «Понижаемая экспрессия мРНК, связанного с Agouti, белком (AGRP) в ядре гипоталамуса дугообразного ядра гиперфагической и ожиренной мышей/ванны». Исследование мозга. Молекулярное исследование мозга . 125 (1–2): 129–39. doi : 10.1016/j.molbrainres.2004.03.012 . PMID 15193430 .
Внешние ссылки
[ редактировать ]- Связанный с Aguti+белок в Национальной медицинской библиотеке Медицинской библиотеки США (Mesh)
- человека Местоположение генома AGRP и AGRP страница сведений генов в браузере генома UCSC .
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