The role of the Agouti-related protein in energy balance regulation

Cellular and Molecular Life Sciences

Volumn 65, Issue 17, 2008, Pages 2721-2731

  Ilnytska, O ^a   Argyropoulos, G ^a  

^a PENNINGTON BIOMEDICAL RESEARCH CENTER   (United States)

Author keywords

Adrenal gland; Hypothalamus; Longevity; Polymorphism

Indexed keywords

AGOUTI RELATED PROTEIN; GHRELIN; GLUCOCORTICOID; INSULIN; LEPTIN;

DISEASE ASSOCIATION; DRUG MECHANISM; ENERGY BALANCE; ENERGY EXPENDITURE; FOOD INTAKE; GENE MUTATION; GENETIC ASSOCIATION; GENETIC RESISTANCE; HUMAN; HYPERPHAGIA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRADER WILLI SYNDROME; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; RNA INTERFERENCE; SINGLE NUCLEOTIDE POLYMORPHISM;

AGOUTI-RELATED PROTEIN; ANIMALS; ENERGY METABOLISM; HUMANS; MODELS, ANIMAL; PHENOTYPE; POLYMORPHISM, GENETIC;

AGOUTI; MUS;

EID: 51349114141     PISSN: 1420682X     EISSN: 15691632     Source Type: Journal    
DOI: 10.1007/s00018-008-8104-4     Document Type: Review

References (127)

1. Ollmann, M. M., Wilson, B. D., Yang, Y. K., Kerns, J. A., Chen, Y., Gantz, I. and Barsh, G. S. (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135-8.
2. Shutter, J. R., Graham, M., Kinsey, A. C., Scully, S., Luthy, R. and Stark, K. L. (1997) Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 11, 593-602.
3. Stutz, A. M., Morrison, C. D. and Argyropoulos, G. (2005) The Agouti-related protein and its role in energy homeostasis. Peptides 26, 1771-81.
4. Vergoni, A. V. and Bertolini, A. (2000) Role of melanocortins in the central control of feeding. Eur. J. Pharmacol. 405, 25-32.
5. MacNeil, D. J., Howard, A. D., Guan, X., Fong, T. M., Nargund, R. P., Bednarek, M. A., Goulet, M. T., Weinberg, D. H., Strack, A. M., Marsh, D. J., Chen, H. Y., Shen, C. P., Chen, A. S., Rosenblum, C. I., MacNeil, T., Tota, M., MacIntyre, E. D. and Van der Ploeg, L. H. (2002) The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. Eur. J. Pharmacol. 440, 141-57.
6. Ellacott, K. L. and Cone, R. D. (2004) The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis. Recent Prog. Horm. Res. 59, 395-408.
7. Zimanyi, I. A. and Pelleymounter, M. A. (2003) The role of melanocortin peptides and receptors in regulation of energy balance. Curr. Pharm. Des. 9, 627-41.
8. Graham, M., Shutter, J. R., Sarmiento, U., Sarosi, I. and Stark, K. L. (1997) Overexpression of Agrt leads to obesity in transgenic mice. Nat. Genet. 17, 273-4.
9. Bewick, G. A., Gardiner, J. V., Dhillo, W. S., Kent, A. S., White, N. E., Webster, Z., Ghatei, M. A. and Bloom, S. R. (2005) Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 19, 1680-2.
10. Gropp, E., Shanabrough, M., Borok, E., Xu, A. W., Janoschek, R., Buch, T., Plum, L., Balthasar, N., Hampel, B., Waisman, A., Barsh, G. S., Horvath, T. L. and Bruning, J. C. (2005) Agouti-related peptide-expressing neurons are mandatory for feeding. Nat. Neurosci. 8, 1289-91.
11. Luquet, S., Perez, F. A., Hnasko, T. S. and Palmiter, R. D. (2005) NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683-5.
12. Mayfield, D. K., Brown, A. M., Page, G. P., Garvey, W. T., Shriver, M. D. and Argyropoulos, G. (2001) A role for the agouti related protein promoter in obesity and type 2 diabetes. Biochem. Biophys. Res. Commun. 287, 568-573.
13. Brown, A. M., Mayfield, D. K., Volaufova, J. and Argyropoulos, G. (2001) The gene structure and minimal promoter of the human agouti related protein. Gene 277, 231-8.
14. Beltramo, M., Campanella, M., Tarozzo, G., Fredduzzi, S., Corradini, L., Forlani, A., Bertorelli, R. and Reggiani, A. (2003) Gene expression profiling of melanocortin system in neuropathic rats supports a role in nociception. Brain Res. Mol. Brain Res. 118, 111-8.
15. Halverson, M. J., Donelan, K. J., Granholm, N. H., Cheesbrough, T. M., Westby, C. A. and Marshall, D. M. (2002) Rapid communication: sequencing of the porcine agouti-related protein (AGRP) gene. J. Anim. Sci. 80, 1388-9.
16. Adam, C. L., Archer, Z. A., Findlay, P. A., Thomas, L. and Marie, M. (2002) Hypothalamic gene expression in sheep for cocaine- and amphetamine-regulated transcript, pro-opiomelanocortin, neuropeptide y, agouti-related Peptide and leptin receptor and responses to negative energy balance. Neuroendocrinology 75, 250-6.
17. Klovins, J., Haitina, T., Fridmanis, D., Kilianova, Z., Kapa, I., Fredriksson, R., Gallo-Payet, N. and Schioth, H. B. (2004) The Melanocortin System in Fugu: Determination of POMC/ AGRP/MCR Gene Repertoire and Synteny, As Well As Pharmacology and Anatomical Distribution of the MCRs. Mol. Biol. Evol. 21, 563-79.
18. Song, Y., Golling, G., Thacker, T. L. and Cone, R. D. (2003) Agouti-related protein (AGRP) is conserved and regulated by metabolic state in the zebrafish, Danio rerio. Endocrine 22, 257-65.
19. Cerda-Reverter, J. M. and Peter, R. E. (2003) Endogenous melanocortin antagonist in fish: structure, brain mapping, and regulation by fasting of the goldfish agouti-related protein gene. Endocrinology 144, 4552-61.
20. Boswell, T., Li, Q. and Takeuchi, S. (2002) Neurons expressing neuropeptide Y mRNA in the infundibular hypothalamus of Japanese quail are activated by fasting and co-express agouti-related protein mRNA. Brain Res. Mol. Brain Res. 100, 31-42.
21. Phillips-Singh, D., Li, Q., Takeuchi, S., Ohkubo, T., Sharp, P. J. and Boswell, T. (2003) Fasting differentially regulates expression of agouti-related peptide, pro-opiomelanocortin, prepro-orexin, and vasoactive intestinal polypeptide mRNAs in the hypothalamus of Japanese quail. Cell. Tissue Res. 313, 217-25.
22. Strader, A. D. and Buntin, J. D. (2003) Changes in agouti-related peptide during the ring dove breeding cycle in relation to prolactin and parental hyperphagia. J. Neuroendocrinol. 15, 1046-53.
23. Strader, A. D., Schioth, H. B. and Buntin, J. D. (2003) The role of the melanocortin system and the melanocortin-4 receptor in ring dove (Streptopelia risoria) feeding behavior. Brain Res. 960, 112-21.
24. Hahn, T. M., Breininger, J. F., Baskin, D. G. and Schwartz, M. W. (1998) Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat. Neurosci. 1, 271-2.
25. Quillan, J. M., Jayawickreme, C. K. and Lerner, M. R. (1995) Combinatorial diffusion assay used to identify topically active melanocyte-stimulating hormone receptor antagonists. Proc. Natl. Acad. Sci. USA 92, 2894-8.
26. Quillan, J. M., Sadee, W., Wei, E. T., Jimenez, C., Ji, L. and Chang, J. K. (1998) A synthetic human Agouti-related protein-(83-132)-NH2 fragment is a potent inhibitor of melanocortin receptor function. FEBS Lett. 428, 59-62.
27. Yang, Y. K., Dickinson, C. J., Zeng, Q., Li, J. Y., Thompson, D. A. and Gantz, I. (1999) Contribution of melanocortin receptor exoloops to Agouti-related protein binding. J. Biol. Chem. 274, 14100-6.
28. Haskell-Luevano, C., Cone, R. D., Monck, E. K. and Wan, Y. P. (2001) Structure activity studies of the melanocortin-4 receptor by in vitro mutagenesis: identification of agouti-related protein (agrp), melanocortin agonist and synthetic peptide antagonist interaction determinants. Biochemistry 40, 6164-79.
29. Haskell-Luevano, C. and Monck, E. K. (2001) Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor. Regul. Pept. 99, 1-7.
30. Thirumoorthy, R., Holder, J. R., Bauzo, R. M., Richards, N. G., Edison, A. S. and Haskell-Luevano, C. (2001) Novel agouti-related-protein-based melanocortin-1 receptor antagonist. J. Med. Chem. 44, 4114-24.
31. Yang, Y. K., Thompson, D. A., Dickinson, C. J., Wilken, J., Barsh, G. S., Kent, S. B. and Gantz, I. (1999) Characterization of Agouti-related protein binding to melanocortin receptors. Mol. Endocrinol. 13, 148-55.
32. Fong, T. M., Mao, C., MacNeil, T., Kalyani, R., Smith, T., Weinberg, D., Tota, M. R. and Van der Ploeg, L. H. (1997) ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem. Biophys. Res. Commun. 237, 629-31.
33. Nijenhuis, W. A., Oosterom, J. and Adan, R. A. (2001) AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol. Endocrinol. 15, 164-71.
34. Jackson, P. J., McNulty, J. C., Yang, Y. K., Thompson, D. A., Chai, B., Gantz, I., Barsh, G. S. and Millhauser, G. L. (2002) Design, Pharmacology, and NMR Structure of a Minimized Cystine Knot with Agouti-Related Protein Activity. Biochemistry 41, 7565-7572.
35. Millhauser, G. L., McNulty, J. C., Jackson, P. J., Thompson, D. A., Barsh, G. S. and Gantz, I. (2003) Loops and links: structural insights into the remarkable function of the agouti-related protein. Ann. NY Acad. Sci. 994, 27-35.
36. Joseph, C. G., Bauzo, R. M., Xiang, Z., Shaw, A. M., Millard, W. J. and Haskell-Luevano, C. (2003) Elongation studies of the human agouti-related protein (AGRP) core decapeptide (Yc[CRFFNAFC]Y) results in antagonism at the mouse melanocortin-3 receptor. Peptides 24, 263-70.
37. Creemers, J. W., Pritchard, L. E., Gyte, A., Le Rouzic, P., Meulemans, S., Wardlaw, S. L., Zhu, X., Steiner, D. F., Davies, N., Armstrong, D., Lawrence, C. B., Luckman, S. M., Schmitz, C. A., Davies, R. A., Brennand, J. C. and White, A. (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, 1621-31.
38. Lee, M., Kim, A., Conwell, I. M. and Wardlaw, S. L. (2006) in: The Endocrine Society 88th Annual Meeting, Vol. P1-243 The Endocrine Society Press, Boston, MA.
39. Goto, K., Inui, A., Takimoto, Y., Yuzuriha, H., Asakawa, A., Kawamura, Y., Tsuji, H., Takahara, Y., Takeyama, C., Katsuura, G. and Kasuga, M. (2003) Acute intracerebroventricular administration of either carboxyl-terminal or amino-terminal fragments of agouti-related peptide produces a long-term decrease in energy expenditure in rats. Int. J. Mol. Med. 12, 379-83.
40. Reizes, O., Lincecum, J., Wang, Z., Goldberger, O., Huang, L., Kaksonen, M., Ahima, R., Hinkes, M. T., Barsh, G. S., Rauvala, H. and Bernfield, M. (2001) Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell 106, 105-16.
41. Reizes, O., Benoit, S. C., Strader, A. D., Clegg, D. J., Akunuru, S. and Seeley, R. J. (2003) Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway. Ann. NY Acad. Sci. 994, 66-73.
42. Schwartz, M. W., Baskin, D. G., Bukowski, T. R., Kuijper, J. L., Foster, D., Lasser, G., Prunkard, D. E., Porte, D., Jr., Woods, S. C., Seeley, R. J. and Weigle, D. S. (1996) Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45, 531-5.
43. Broberger, C., Johansen, J., Johansson, C., Schalling, M. and Hokfelt, T. (1998) The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc. Natl. Acad. Sci. USA 95, 15043-8.
44. Wilson, B. D., Ollmann, M. M. and Barsh, G. S. (1999) The role of agouti-related protein in regulating body weight. Mol. Med. Today 5, 250-6.
45. Bruning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Muller-Wieland, D. and Kahn, C. R. (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122-5.
46. van den Top, M., Lee, K., Whyment, A. D., Blanks, A. M. and Spanswick, D. (2004) Orexigen-sensitive NPY/AgRP pace-maker neurons in the hypothalamic arcuate nucleus. Nat. Neurosci. 7, 493-4.
47. Bouret, S. G., Draper, S. J. and Simerly, R. B. (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108-10.
48. Minokoshi, Y. and Kahn, B. B. (2003) Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle. Biochem. Soc. Trans. 31, 196-201.
49. Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y. B., Lee, A., Xue, B., Mu, J., Foufelle, F., Ferre, P., Birnbaum, M. J., Stuck, B. J. and Kahn, B. B. (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature.
50. Niswender, K. D., Gallis, B., Blevins, J. E., Corson, M. A., Schwartz, M. W. and Baskin, D. G. (2003) Immunocytochemical detection of phosphatidylinositol 3-kinase activation by insulin and leptin. J. Histochem. Cytochem. 51, 275-83.
51. Niswender, K. D., Morrison, C. D., Clegg, D. J., Olson, R., Baskin, D. G., Myers, M. G., Jr., Seeley, R. J. and Schwartz, M. W. (2003) Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52, 227-31.
52. Gao, Q., Wolfgang, M. J., Neschen, S., Morino, K., Horvath, T. L., Shulman, G. I. and Fu, X. Y. (2004) Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation. Proc. Natl. Acad. Sci. USA 101, 4661-6.
53. Bjorbaek, C. and Kahn, B. B. (2004) Leptin signaling in the central nervous system and the periphery. Recent Prog. Horm. Res. 59, 305-31.
54. Hegyi, K., Fulop, K., Kovacs, K., Toth, S. and Falus, A. (2004) Leptin-induced signal transduction pathways. Cell. Biol. Int. 28, 159-69.
55. Hakansson-Ovesjo, M. L., Collin, M. and Meister, B. (2000) Down-regulated STAT3 messenger ribonucleic acid and STAT3 protein in the hypothalamic arcuate nucleus of the obese leptin-deficient (ob/ob) mouse. Endocrinology 141, 3946-55.
56. Mesaros, A., Koralov, S. B., Rother, E., Wunderlich, F. T., Ernst, M. B., Barsh, G. S., Rajewsky, K. and Bruning, J. C. (2008) Activation of Stat3 Signaling in AgRP Neurons Promotes Locomotor Activity. Cell. Metab. 7, 236-248.
57. Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H. and Kangawa, K. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656-60.
58. Tschop, M., Smiley, D. L. and Heiman, M. L. (2000) Ghrelin induces adiposity in rodents. Nature 407, 908-13.
59. Kamegai, J., Tamura, H., Shimizu, T., Ishii, S., Sugihara, H. and Wakabayashi, I. (2001) Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 50, 2438-43.
60. Kamegai, J., Tamura, H., Ishii, S., Sugihara, H. and Wakabayashi, I. (2001) Thyroid hormones regulate pituitary growth hormone secretagogue receptor gene expression. J. Neuroendocrinol. 13, 275-8.
61. Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K. and Matsukura, S. (2001) A role for ghrelin in the central regulation of feeding. Nature 409, 194-8.
62. Wren, A. M., Small, C. J., Abbott, C. R., Dhillo, W. S., Seal, L. J., Cohen, M. A., Batterham, R. L., Taheri, S., Stanley, S. A., Ghatei, M. A. and Bloom, S. R. (2001) Ghrelin causes hyperphagia and obesity in rats. Diabetes 50, 2540-7.
63. Kamegai, J., Tamura, H., Shimizu, T., Ishii, S., Sugihara, H. and Wakabayashi, I. (2000) Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 141, 4797-800.
64. Chen, H. Y., Trumbauer, M. E., Chen, A. S., Weingarth, D. T., Adams, J. R., Frazier, E. G., Shen, Z., Marsh, D. J., Feighner, S. D., Guan, X. M., Ye, Z., Nargund, R. P., Smith, R. G., Van Der Ploeg, L. H., Howard, A. D., MacNeil, D. J. and Qian, S. (2004) Orexigenic Action of Peripheral Ghrelin is Mediated by Neuropeptide Y (NPY) and Agouti-Related Protein (AgRP). Endocrinology.
65. Wortley, K. E., Anderson, K., Garcia, K., Murray, J., Malinova, L., Liu, R., Moncrieffe, M., Thabet, K., Cox, H., Yancopoulos, G. D., Wiegand, S. J. and Sleeman, M. W. (2004) Deletion of ghrelin reveals no effect on food intake, but a primary role in energy balance. Obes. Res. 12, 170.
66. Drazen, D. L., Wortman, M. D., Schwartz, M. W., Clegg, D. J., van Dijk, G., Woods, S. C. and Seeley, R. J. (2003) Adrenalectomy alters the sensitivity of the central nervous system melanocortin system. Diabetes 52, 2928-34.
67. Zakrzewska, K. E., Sainsbury, A., Cusin, I., Rouru, J., Jeanrenaud, B. and Rohner-Jeanrenaud, F. (1999) Selective dependence of intracerebroventricular neuropeptide Y-elicited effects on central glucocorticoids. Endocrinology 140, 3183-7.
68. Madiehe, A. M., Lin, L., White, C., Braymer, H. D., Bray, G. A. and York, D. A. (2001) Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R2048-58.
69. Lu, X. Y., Shieh, K. R., Kabbaj, M., Barsh, G. S., Akil, H. and Watson, S. J. (2002) Diurnal rhythm of agouti-related protein and its relation to corticosterone and food intake.PG - 3905-15. Endocrinology 143.
70. Jeanrenaud, B. and Rohner-Jeanrenaud, F. (2000) CNS-periphery relationships and body weight homeostasis: influence of the glucocorticoid status. Int. J. Obes. Relat. Metab. Disord. 24 Suppl. 2, S74-6.
71. Rocha, M., Bing, C., Williams, G. and Puerta, M. (2003) Pregnancy-induced hyperphagia is associated with increased gene expression of hypothalamic agouti-related peptide in rats. Regul. Pept. 114, 159-65.
72. Sorensen, A., Adam, C. L., Findlay, P. A., Marie, M., Thomas, L., Travers, M. T. and Vernon, R. G. (2002) Leptin secretion and hypothalamic neuropeptide and receptor gene expression in sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1227-35.
73. Ge, Y., Ohta, T., Driscoll, D. J., Nicholls, R. D. and Kalra, S. P. (2002) Anorexigenic melanocortin signaling in the hypothalamus is augmented in association with failure-to-thrive in a transgenic mouse model for Prader-Willi syndrome. Brain Res. 957, 42-5.
74. Hillebrand, J. J., Kas, M. J., Scheurink, A. J., van Dijk, G. and Adan, R. A. (2006) AgRP(83-132) and SHU9119 differently affect activity-based anorexia. Eur. Neuropsychopharmacol. 16, 403-12.
75. Marks, D. L. and Cone, R. D. (2001) Central melanocortins and the regulation of weight during acute and chronic disease. Recent Prog. Horm. Res. 56, 359-75.
76. Xiao, E., Xia-Zhang, L., Vulliemoz, N. R., Ferin, M. and Wardlaw, S. L. (2003) Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate. Endocrinology 144, 1736-41.
77. Dandona, P., Aljada, A. and Bandyopadhyay, A. (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25, 4-7.
78. Fekete, C., Sarkar, S., Rand, W. M., Harney, J. W., Emerson, C. H., Bianco, A. C. and Lechan, R. M. (2002) Agouti-related protein (AGRP) has a central inhibitory action on the hypothalamic-pituitary-thyroid (HPT) axis; comparisons between the effect of AGRP and neuropeptide Y on energy homeostasis and the HPTaxis. Endocrinology 143, 3846-53.
79. Graunke, D. M. and Argyropoulos, G. (2003) Deciphering Transcriptional Regulation Relevant to Eating Behavior. Curr. Genom. 4, 623-633.
80. Bicknell, A. B., Lomthaisong, K., Gladwell, R. T. and Lowry, P. J. (2000) Agouti related protein in the rat adrenal cortex: implications for novel autocrine mechanisms modulating the actions of pro- opiomelanocortin peptides. J. Neuroendocrinol. 12, 977-82.
81. Katsuki, A., Sumida, Y., Gabazza, E. C., Murashima, S., Tanaka, T., Furuta, M., Araki-Sasaki, R., Hori, Y., Nakatani, K., Yano, Y. and Adachi, Y. (2001) Plasma levels of agouti-related protein are increased in obese men. J. Clin. Endocrinol. Metab. 86, 1921-4.
82. Shen, C. P., Wu, K. K., Shearman, L. P., Camacho, R., Tota, M. R., Fong, T. M. and Van Der Ploeg, L. H. (2002) Plasma agouti-related protein level: a possible correlation with fasted and fed States in humans and rats. J. Neuroendocrinol. 14, 607-10.
83. Kastin, A. J., Akerstrom, V. and Hackler, L. (2000) Agouti-related protein(83-132) aggregates and crosses the blood-brain barrier slowly. Metabolism 49, 1444-8.
84. Claycombe, K. J., Wang, Y., Jones, B. H., Kim, S., Wilkison, W. O., Zemel, M. B., Chun, J. and Moustaid-Moussa, N. (2000) Transcriptional regulation of the adipocyte fatty acid synthase gene by agouti: interaction with insulin. Physiol. Genomics 3, 157-62.
85. Claycombe, K. J., Xue, B. Z., Mynatt, R. L., Zemel, M. B. and Moustaid-Moussa, N. (2000) Regulation of leptin by agouti. Physiol. Genomics 2, 101-5.
86. Ebihara, K., Ogawa, Y., Katsuura, G., Numata, Y., Masuzaki, H., Satoh, N., Tamaki, M., Yoshioka, T., Hayase, M., Matsuoka, N., Aizawa-Abe, M., Yoshimasa, Y. and Nakao, K. (1999) Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action. Diabetes 48, 2028-33.
87. Hoggard, N., Hunter, L., Duncan, J. S. and Rayner, D. V. (2004) Regulation of adipose tissue leptin secretion by alpha-melanocyte-stimulating hormone and agouti-related protein: further evidence of an interaction between leptin and the melanocortin signalling system. J Mol. Endocrinol. 32, 145-53.
88. Dhillo, W. S., Small, C. J., Gardiner, J. V., Bewick, G. A., Whitworth, E. J., Jethwa, P. H., Seal, L. J., Ghatei, M. A., Hinson, J. P. and Bloom, S. R. (2003) Agouti-related protein has an inhibitory paracrine role in the rat adrenal gland. Biochem. Biophys. Res. Commun. 301, 102-7.
89. Doghman, M., Delagrange, P., Blondet, A., Berthelon, M. C., Durand, P., Naville, D. and Begeot, M. (2003) Agouti-Related Protein Antagonizes Glucocorticoid Production Induced through Mc4-R Activation in Bovine Adrenal Cells: A Possible Autocrine Control. Endocrinology.
90. Takeuchi, S. and Takahashi, S. (1999) A possible involvement of melanocortin 3 receptor in the regulation of adrenal gland function in the chicken. Biochim. Biophys. Acta 1448, 512-8.
91. Takeuchi, S., Teshigawara, K. and Takahashi, S. (2000) Widespread expression of Agouti-related protein (AGRP) in the chicken: a possible involvement of AGRP in regulating peripheral melanocortin systems in the chicken. Biochim. Biophys. Acta 1496, 261-9.
92. Korner, J., Wissig, S., Kim, A., Conwell, I. M. and Wardlaw, S. L. (2003) Effects of agouti-related protein on metabolism and hypothalamic neuropeptide gene expression. J. Neuroendocrinol. 15, 1116-21.
93. Backberg, M., Madjid, N., Ogren, S. O. and Meister, B. (2004) Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice. Brain Res. Mol. Brain Res. 125, 129-39.
94. Smith Richards, B. K., Belton, B. N., Poole, A. C., Mancuso, J. J., Churchill, G. A., Li, R., Volaufova, J., Zuberi, A. and York, B. (2002) QTL analysis of self-selected macronutrient diet intake: fat, carbohydrate, and total kilocalories. Physiol. Genomics 11, 205-17.
95. York, B., Lei, K. and West, D. B. (1996) Sensitivity to dietary obesity linked to a locus on chromosome 15 in a CAST/Ei x C57BL/6J F2 intercross. Mamm. Genome 7, 677-81.
96. York, B., Truett, A. A., Monteiro, M. P., Barry, S. J., Warden, C. H., Naggert, J. K., Maddatu, T. P. and West, D. B. (1999) Gene-environment interaction: a significant diet-dependent obesity locus demonstrated in a congenic segment on mouse chromosome 7. Mamm. Genome 10, 457-62.
97. Breit, A., Wolff, K., Kalwa, H., Jarry, H., Buch, T. and Gudermann, T. (2006) The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and -4 receptors. J. Biol. Chem..
98. Tolle, V. and Low, M. J. (2007) In vivo evidence for inverse agonism of agouti related peptide in the central nervous system of proopiomelanocortin deficient mice. Diabetes.
99. Makimura, H., Mizuno, T. M., Mastaitis, J. W., Agami, R. and Mobbs, C. V. (2002) Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake. BMC Neurosci. 3, 18.
100. Xiang, L., Murai, A. and Muramatsu, T. (2004) The effects of agouti-related protein gene transfer in vivo by electroporation in mice. Neurosci. Lett. 370, 108-13.
101. Qian, S., Chen, H., Weingarth, D., Trumbauer, M. E., Novi, D. E., Guan, X., Yu, H., Shen, Z., Feng, Y., Frazier, E., Chen, A., Camacho, R. E., Shearman, L. P., Gopal-Truter, S., MacNeil, D. J., Van Der Ploeg, L. H. and Marsh, D. J. (2002) Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice. Mol. Cell. Biol. 22, 5027-35.
102. Flier, J. S. (2006) AgRP in energy balance: Will the real AgRP please stand up? Cell. Metab. 3, 83-5.
103. Wortley, K. E., Anderson, K. D., Yasenchak, J., Murphy, A., Valenzuela, D., Diano, S., Yancopoulos, G. D., Wiegand, S. J. and Sleeman, M. W. (2005) Agouti-related protein-deficient mice display an age-related lean phenotype. Cell. Metab. 2, 421-7.
104. Redmann, S. M., Jr. and Argyropoulos, G. (2006) AgRP-deficiency could lead to increased lifespan. Biochem. Biophys. Res. Commun. 351, 860-864.
105. Small, C. J., Kim, M. S., Stanley, S. A., Mitchell, J. R., Murphy, K., Morgan, D. G., Ghatei, M. A. and Bloom, S. R. (2001) Effects of chronic central nervous system administration of agouti- related protein in pair-fed animals. Diabetes 50, 248-54.
106. Wu, Q., Howell, M. P., Cowley, M. A. and Palmiter, R. D. (2008) Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc. Natl. Acad. Sci. USA 105, 2687-92.
107. Fetissov, S. O., Bergstrom, U., Johansen, J. E., Hokfelt, T., Schalling, M. and Ranscht, B. (2005) Alterations of arcuate nucleus neuropeptidergic development in contactin-deficient mice: comparison with anorexia and food-deprived mice. Eur. J. Neurosci. 22, 3217-28.
108. Johansen, J. E., Fetissov, S. O., Bergstrom, U., Nilsson, I., Fay, C., Ranscht, B., Hokfelt, T. and Schalling, M. (2007) Evidence for hypothalamic dysregulation in mouse models of anorexia as well as in humans. Physiol. Behav. 92, 278-82.
109. Lachuer, J., Ouyang, L., Legras, C., DelRio, J. and Barlow, C. (2005) Gene expression profiling reveals an inflammatory process in the anx/anx mutant mice. Brain Res. Mol. Brain Res. 139, 372-6.
110. Bai, F., Rankinen, T., Charbonneau, C., Belsham, D. D., Rao, D. C., Bouchard, C. and Argyropoulos, G. (2004) Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium. J. Med. Genet. 41, 350-3.
111. Argyropoulos, G., Rankinen, T., Bai, F., Rice, T., Province, M., Leon, A., Skinner, J., Wilmore, J., Rao, D. and Bouchard, B. (2003) The agouti related protein and body fatness in humans. International Journal of Obesity 27, 276-280.
112. Vaisse, C., Clement, K., Durand, E., Hercberg, S., Guy-Grand, B. and Froguel, P. (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253-62.
113. 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. and Adan, R. A. (2001) Association between an agouti-related protein gene polymorphism and anorexia nervosa. Mol. Psychiatry 6, 325-8.
114. Dubern, B., Clement, K., Pelloux, V., Froguel, P., Girardet, J. P., Guy-Grand, B. and Tounian, P. (2001) Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. J. Pediatr. 139, 204-9.
115. Marks, D. L., Boucher, N., Lanouette, C. M., Perusse, L., Brookhart, G., Comuzzie, A. G., Chagnon, Y. C. and Cone, R. D. (2004) Ala67Thr polymorphism in the Agouti-related peptide gene is associated with inherited leanness in humans. Am J. Med. Genet. 126A, 267-71.
116. Tracy, A. L., Clegg, D. J., Johnson, J. D., Davidson, T. L. and Benoit, S. C. (2007) The melanocortin antagonist AgRP (83-132) increases appetitive responding for a fat, but not a carbohydrate, reinforcer. Pharmacol. Biochem. Behav.
117. Sozen, M. A., de Jonge, L. H., Greenway, F., Ravussin, E., Smith, S. R. and Argyropoulos, G. (2006) A rare mutation in AgRP, +79G>A, affects promoter activity. Eur. J. Clin. Nutr.
118. Hoggard, N., Rayner, D. V., Johnston, S. L. and Speakman, J. R. (2004) Peripherally administered [Nle4,D-Phe7]-alpha-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice. J Mol. Endocrinol. 33, 693-703.
119. Gavrila, A., Chan, J. L., Miller, L. C., Heist, K., Yiannakouris, N. and Mantzoros, C. S. (2005) 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. J. Clin. Endocrinol. Metab. 90, 1047-54.
120. Rossi, M., Kim, M. S., Morgan, D. G., Small, C. J., Edwards, C. M., Sunter, D., Abusnana, S., Goldstone, A. P., Russell, S. H., Stanley, S. A., Smith, D. M., Yagaloff, K., Ghatei, M. A. and Bloom, S. R. (1998) A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139, 4428-31.
121. Hagan, M. M., Rushing, P. A., Pritchard, L. M., Schwartz, M. W., Strack, A. M., Van Der Ploeg, L. H., Woods, S. C. and Seeley, R. J. (2000) Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R47-52.
122. 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. and Karbon, W. (1998) Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein. Biochemistry 37, 16041-52.
123. Small, C. J., Liu, Y. L., Stanley, S. A., Connoley, I. P., Kennedy, A., Stock, M. J. and Bloom, S. R. (2003) Chronic CNS administration of Agouti-related protein (Agrp) reduces energy expenditure. Int. J. Obes. Relat. Metab. Disord. 27, 530-3.
124. Kim, M. S., Rossi, M., Abbott, C. R., AlAhmed, S. H., Smith, D. M. and Bloom, S. R. (2002) Sustained orexigenic effect of Agouti related protein may be not mediated by the melanocortin 4 receptor. Peptides 23, 1069-76.
125. Zheng, H., Corkern, M. M., Crousillac, S. M., Patterson, L. M., Phifer, C. B. and Berthoud, H. R. (2002) Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP. Am. J. Physiol. Regul. Integr. Comp. Physiol. 282, R1773-81.
126. Nilsson, I., Lindfors, C., Fetissov, S. O., Hokfelt, T. and Johansen, J. E. (2008) Aberrant agouti-related protein system in the hypothalamus of the anx/anx mouse is associated with activation of microglia. J. Comp. Neurol. 507, 1128-40.
127. Argyropoulos, G., Rankinen, T., Neufeld, D. R., Rice, T., Province, M. A., Leon, A. S., Skinner, J. S., Wilmore, J. H., Rao, D. C. and Bouchard, C. (2002) A polymorphism in the human agouti-related protein is associated with late-onset obesity. J. Clin. Endocrinol. Metab. 87, 4198-202.