Diabetes, Vol 48, Issue 10 2028-2033, Copyright © 1999 by American Diabetes Association

ARTICLES

Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action

K Ebihara, Y Ogawa, G Katsuura, Y Numata, H Masuzaki, N Satoh, M Tamaki, T Yoshioka, M Hayase, N Matsuoka, M Aizawa-Abe, Y Yoshimasa and K Nakao
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.

To understand the role of agouti-related protein (AGRP), an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action, we produced a full-length recombinant AGRP and examined its effect on the satiety effect of leptin. We also studied leptin's regulation of hypothalamic AGRP mRNA expression. A single intracerebroventricular (i.c.v.) injection of AGRP significantly increased cumulative food intake and body weight in a dose-dependent manner in rats. The leptin-induced inhibition of food intake and body weight was reversed by co-injection of AGRP in a dose-dependent manner. Hypothalamic AGRP mRNA expression was upregulated in leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice and downregulated in lethal yellow agouti mice (KKAy mice) with hyperleptinemia. A single i.c.v. injection of leptin reversed the increased AGRP mRNA levels in ob/ob mice but not in db/db mice. In control mice and KKAy mice, AGRP mRNA expression was upregulated during fasting, when plasma leptin concentrations were decreased. No significant increase in AGRP mRNA expression was noted during fasting in control mice and KKAy mice treated with leptin. This study provides the first direct evidence that AGRP is a negative regulator of leptin action, and leptin downregulates hypothalamic AGRP production. Because leptin is shown to increase hypothalamic alpha-melanocyte stimulating hormone (alpha-MSH) production, our data suggest that its action via the hypothalamic melanocortin system is determined by the balance between the levels of its agonist and antagonist, alpha-MSH and AGRP.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Crane, N. Akhter, B. W. Johnson, M. Iruthayanathan, F. Syed, A. Kudo, Y.-H. Zhou, and G. V. Childs Fasting and Glucose Effects on Pituitary Leptin Expression: Is Leptin a Local Signal for Nutrient Status? J. Histochem. Cytochem., October 1, 2007; 55(10): 1059 - 1073. [Abstract] [Full Text] [PDF]

				K. Nonogaki, K. Nozue, and Y. Oka Social Isolation Affects the Development of Obesity and Type 2 Diabetes in Mice Endocrinology, October 1, 2007; 148(10): 4658 - 4666. [Abstract] [Full Text] [PDF]

				K. Nonogaki, K. Nozue, and Y. Oka Hyperphagia Alters Expression of Hypothalamic 5-HT2C and 5-HT1B Receptor Genes and Plasma Des-Acyl Ghrelin Levels in Ay Mice Endocrinology, December 1, 2006; 147(12): 5893 - 5900. [Abstract] [Full Text] [PDF]

				J. W. M. Creemers, L. E. Pritchard, A. Gyte, P. Le Rouzic, S. Meulemans, S. L. Wardlaw, X. Zhu, D. F. Steiner, N. Davies, D. Armstrong, et al. 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, April 1, 2006; 147(4): 1621 - 1631. [Abstract] [Full Text] [PDF]

				K. Gotoh, M. Liu, S. C. Benoit, D. J. Clegg, W. S. Davidson, D. D'Alessio, R. J. Seeley, P. Tso, and S. C. Woods Apolipoprotein A-IV interacts synergistically with melanocortins to reduce food intake Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R202 - R207. [Abstract] [Full Text] [PDF]

				W. Pan, A. J. Kastin, Y. Yu, C. M. Cain, T. Fairburn, A. M. Stutz, C. Morrison, and G. Argyropoulos Selective Tissue Uptake of Agouti-Related Protein(82-131) and Its Modulation by Fasting Endocrinology, December 1, 2005; 146(12): 5533 - 5539. [Abstract] [Full Text] [PDF]

				R. J. Loos, T. Rankinen, T. Rice, D. Rao, A. S Leon, J. S Skinner, C. Bouchard, and G. Argyropoulos Two ethnic-specific polymorphisms in the human Agouti-related protein gene are associated with macronutrient intake Am. J. Clinical Nutrition, November 1, 2005; 82(5): 1097 - 1101. [Abstract] [Full Text] [PDF]

				W. A. Blom, A. Stafleu, C. de Graaf, F. J Kok, G. Schaafsma, and H. F. Hendriks Ghrelin response to carbohydrate-enriched breakfast is related to insulin Am. J. Clinical Nutrition, February 1, 2005; 81(2): 367 - 375. [Abstract] [Full Text] [PDF]

				A. Gavrila, J. L. Chan, L. C. Miller, K. Heist, N. Yiannakouris, and C. S. Mantzoros 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., February 1, 2005; 90(2): 1047 - 1054. [Abstract] [Full Text] [PDF]

				L. S. Tallam, J. J. Kuo, A. A. da Silva, and J. E. Hall Cardiovascular, Renal, and Metabolic Responses to Chronic Central Administration of Agouti-Related Peptide Hypertension, December 1, 2004; 44(6): 853 - 858. [Abstract] [Full Text] [PDF]

				T. Wolden-Hanson, B. T. Marck, and A. M. Matsumoto Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding responses to AgRP in aging male Brown Norway rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R138 - R146. [Abstract] [Full Text] [PDF]

				F Bai, T Rankinen, C Charbonneau, D D Belsham, D C Rao, C Bouchard, and G Argyropoulos Functional dimorphism of two hAgRP promoter SNPs in linkage disequilibrium J. Med. Genet., May 1, 2004; 41(5): 350 - 353. [Abstract] [Full Text] [PDF]

				F. F. Chehab, J. Qiu, and S. Ogus The Use of Animal Models to Dissect the Biology of Leptin Recent Prog. Horm. Res., January 1, 2004; 59(1): 245 - 266. [Abstract] [Full Text]

				C. Bjorbaek and B. B. Kahn Leptin Signaling in the Central Nervous System and the Periphery Recent Prog. Horm. Res., January 1, 2004; 59(1): 305 - 331. [Abstract] [Full Text]

				T. Masaki, G. Yoshimichi, S. Chiba, T. Yasuda, H. Noguchi, T. Kakuma, T. Sakata, and H. Yoshimatsu Corticotropin-Releasing Hormone-Mediated Pathway of Leptin to Regulate Feeding, Adiposity, and Uncoupling Protein Expression in Mice Endocrinology, August 1, 2003; 144(8): 3547 - 3554. [Abstract] [Full Text] [PDF]

				T. Masaki, S. Chiba, G. Yoshimichi, T. Yasuda, H. Noguchi, T. Kakuma, T. Sakata, and H. Yoshimatsu Neuronal Histamine Regulates Food Intake, Adiposity, and Uncoupling Protein Expression in Agouti Yellow (Ay/a) Obese Mice Endocrinology, June 1, 2003; 144(6): 2741 - 2748. [Abstract] [Full Text] [PDF]

				I. Swart, J. W. Jahng, J. M. Overton, and T. A. Houpt Hypothalamic NPY, AGRP, and POMC mRNA responses to leptin and refeeding in mice Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2002; 283(5): R1020 - R1026. [Abstract] [Full Text] [PDF]

				G. Argyropoulos, T. Rankinen, D. R. Neufeld, T. Rice, M. A. Province, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, and C. Bouchard A Polymorphism in the Human Agouti-Related Protein Is Associated with Late-Onset Obesity J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4198 - 4202. [Abstract] [Full Text] [PDF]

				Y. Tsuruta, H. Yoshimatsu, S. Hidaka, S. Kondou, K. Okamoto, and T. Sakata Hyperleptinemia in Ay/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E967 - E973. [Abstract] [Full Text] [PDF]

				H. Kobayashi, Y. Ogawa, M. Shintani, K. Ebihara, M. Shimodahira, T. Iwakura, M. Hino, T. Ishihara, K. Ikekubo, H. Kurahachi, et al. A Novel Homozygous Missense Mutation of Melanocortin-4 Receptor (MC4R) in a Japanese Woman With Severe Obesity Diabetes, January 1, 2002; 51(1): 243 - 246. [Abstract] [Full Text] [PDF]

				J. Kamegai, H. Tamura, T. Shimizu, S. Ishii, H. Sugihara, and I. Wakabayashi Chronic Central Infusion of Ghrelin Increases Hypothalamic Neuropeptide Y and Agouti-Related Protein mRNA Levels and Body Weight in Rats Diabetes, November 1, 2001; 50(11): 2438 - 2443. [Abstract] [Full Text] [PDF]

				S. Aja, G. J. Schwartz, M. J. Kuhar, and T. H. Moran Intracerebroventricular CART peptide reduces rat ingestive behavior and alters licking microstructure Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1613 - R1619. [Abstract] [Full Text] [PDF]

				A. Katsuki, Y. Sumida, E. C. Gabazza, S. Murashima, T. Tanaka, M. Furuta, R. Araki-Sasaki, Y. Hori, K. Nakatani, Y. Yano, et al. Plasma Levels of Agouti-Related Protein Are Increased in Obese Men J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1921 - 1924. [Abstract] [Full Text]

				H. Makimura, T. M. Mizuno, X.-J. Yang, J. Silverstein, J. Beasley, and C. V. Mobbs Cerulenin Mimics Effects of Leptin on Metabolic Rate, Food Intake, and Body Weight Independent of the Melanocortin System, but Unlike Leptin, Cerulenin Fails to Block Neuroendocrine Effects of Fasting Diabetes, April 1, 2001; 50(4): 733 - 739. [Abstract] [Full Text]

				J. M. Overton, T. D. Williams, J. B. Chambers, and M. E. Rashotte Cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2001; 280(4): R1007 - R1015. [Abstract] [Full Text] [PDF]

				M. Shintani, Y. Ogawa, K. Ebihara, M. Aizawa-Abe, F. Miyanaga, K. Takaya, T. Hayashi, G. Inoue, K. Hosoda, M. Kojima, et al. Ghrelin, an Endogenous Growth Hormone Secretagogue, Is a Novel Orexigenic Peptide That Antagonizes Leptin Action Through the Activation of Hypothalamic Neuropeptide Y/Y1 Receptor Pathway Diabetes, February 1, 2001; 50(2): 227 - 232. [Abstract] [Full Text]

				C. J. Small, M. S. Kim, S. A. Stanley, J. R.D. Mitchell, K. Murphy, D. G.A. Morgan, M. A. Ghatei, and S. R. Bloom Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals Diabetes, February 1, 2001; 50(2): 248 - 254. [Abstract] [Full Text]

				T. Masaki, H. Yoshimatsu, S. Chiba, T. Watanabe, and T. Sakata Central Infusion of Histamine Reduces Fat Accumulation and Upregulates UCP Family in Leptin-Resistant Obese Mice Diabetes, February 1, 2001; 50(2): 376 - 384. [Abstract] [Full Text]

				W. A. J. Nijenhuis, J. Oosterom, and R. A. H. Adan AgRP(83-132) Acts as an Inverse Agonist on the Human-Melanocortin-4 Receptor Mol. Endocrinol., January 1, 2001; 15(1): 164 - 171. [Abstract] [Full Text]

				H. C. SLAVKIN OBESITY, BRAIN AND GONADAL FUNCTIONS, AND OSTEOPOROSIS J Am Dent Assoc, May 1, 2000; 131(5): 673 - 677. [Full Text] [PDF]