Cited by 580Regulation of Appetite and ObesityNeuropeptides and Animal PhysiologyHypothalamic control of reproductive hormones

The DOI matches its Crossref record.

A C-Terminal Fragment of Agouti-Related Protein Increases Feeding and Antagonizes the Effect of Alpha-Melanocyte Stimulating Hormone in Vivo

Rossi, M., Kim, M. S., Morgan, D. G. A., Small, C. J., Edwards, C. M. B., Sunter, D., Abusnana, S., Goldstone, A. P., Russell, S. H., Stanley, S. A., Smith, D. M., Yagaloff, K., Ghatei, M. A., Bloom, S. R.·1998·Endocrinology

DOI 10.1210/endo.139.10.6332

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Abstract

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.

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Influential
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BackgroundSelf-citation
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BackgroundInfluential
Association of cocaine- and amphetamine-regulated transcript-immunoreactive elements with thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and its role in the regulation of the hypothalamic-pituitary-thyroid axis during fasting
Fekete, C., Mihály, E., Luo, L.-G., Kelly, J., Clausen, J. T., Mao, Q., Rand, W. M., Moss, L. G., Kuhar, M., Emerson, C. H., et al. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-24-09224.2000 · Cited by 163
“melanocortin receptors (Rossi et al., 1998), is capable of restoring TRH mRNA content in the PVN to normal levels when infused intracerebroventricularly to fasted animals, suggesting that a-MSH may stimulate the biosynthesis of TRH (Fekete et al.”
Background
The role of leptin in health and disease
Ramos-Lobo, A. M., & Donato, J. (2017) · Temperature · doi:10.1080/23328940.2017.1327003 · Cited by 172
“Consequently, AgRP blocks the capacity of a-MSH to activate MC3R/MC4R, which also leads to an increase in food intake.(70,77) Finally, several pieces of evidence also indicate that the inhibitory GABAergic transmission of these neurons is important to modulate neural circuits involved in feeding behavior.”
Background
Eating Elicited by Orexin-A, But Not Melanin-Concentrating Hormone, Is Opioid Mediated
Clegg, D. J., Air, E. L., Woods, S. C., & Seeley, R. J. (2002) · Endocrinology · doi:10.1210/endo.143.8.8977 · Cited by 160
“This dose of AgRP elicits a reliable and long-lasting increase in food intake (25, 26, 38).”
Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats
Morton, G. J., Niswender, K. D., Rhodes, C. J., Myers, M. G., Blevins, J. E., Baskin, D. G., & Schwartz, M. W. (2003) · Endocrinology · doi:10.1210/en.2002-0115 · Cited by 158
The central melanocortin system regulates food intake in goldfish
Cerdá‐Reverter, J. M., Schiöth, H. B., & Peter, R. E. (2003) · Regulatory Peptides · doi:10.1016/s0167-0115(03)00144-7 · Cited by 159
Fuel utilization by hypothalamic neurons: roles for ROS
Horváth, T. L., Andrews, Z. B., & Diano, S. (2008) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2008.10.003 · Cited by 165
Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding
Alcantara, I. C., Tapia, A. P. M., Aponte, Y., & Krashes, M. J. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00611-y · Cited by 155
Role of the Central Melanocortin Circuitry in Adaptive Thermogenesis of Brown Adipose Tissue
Voss-Andreae, A., Murphy, J. G., Ellacott, K. L. J., Stuart, R. C., Nillni, E. A., Cone, R. D., & Fan, W. (2006) · Endocrinology · doi:10.1210/en.2006-1389 · Cited by 155
“The dose of AgRP was chosen based on efficacy in previous studies in which icv injection of 1 nmol AgRP (83–132) significantly stimulated food intake ( 34 ).”
Method
Effect of intracerebroventricular α-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression
McMinn, J. E., Wilkinson, C. W., Havel, P. J., Woods, S. C., & Schwartz, M. W. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.2.r695 · Cited by 156
Neuronal control of energy homeostasis
Gao, Q., & Horváth, T. L. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.11.063 · Cited by 160
Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals
Small, C. J., Kim, M. S., Stanley, S. A., Mitchell, J. R. D., Murphy, K. G., Morgan, D. G. A., Ghatei, M. A., & Bloom, S. R. (2001) · Diabetes · doi:10.2337/diabetes.50.2.248 · Cited by 156
“AGRP (83-132), an MC3/4-R antagonist (16,38), was purchased from Phoenix”
BackgroundMethodInfluentialSelf-citation
Nutrition and human health from a sex–gender perspective
Marino, M., Masella, R., Bulzomi, P., Campesi, I., Malorni, W., & Franconi, F. (2011) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.02.001 · Cited by 159
Hypothalamic proopiomelanocortin processing and the regulation of energy balance
Wardlaw, S. L. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.10.107 · Cited by 153
“Creemers et al. have shown PC1/3 is expressed in AgRP neurons and is responsible for the generation of AgRP83–132 (Creemers et al., 2006).”
Influential
Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus
Sergeyev, V., Broberger, C., & Hökfelt, T. G. M. (2001) · Molecular Brain Research · doi:10.1016/s0169-328x(01)00088-2 · Cited by 156
Regulation of Metabolism and Body Fat Mass by Leptin
Baile, C. A., Della‐Fera, M. A., & Martin, R. J. (2000) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.20.1.105 · Cited by 152
Nesfatin-1 increases anxiety- and fear-related behaviors in the rat
Merali, Z., Cayer, C., Kent, P., & Anisman, H. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1252-2 · Cited by 152
“For example, central administration of melanocortin agonists such as α-MSH or MTII reduce food intake ( Rossi et al. 1998; Vergoni and Bertolini 2000).”
Background
Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake
Makimura, H., Mizuno, T. M., Mastaitis, J. W., Agami, R., & Mobbs, C. V. (2002) · BMC Neuroscience · doi:10.1186/1471-2202-3-18 · Cited by 150
“Nevertheless the lack of an effect on food intake was unexpected since treatment with synthetic AGRP peptides has profound effects on food intake [4,5].”
Background
Two important systems in energy homeostasis: melanocortins and melanin-concentrating hormone
Tritos, N. A., & Maratos–Flier, E. (1999) · Neuropeptides · doi:10.1054/npep.1999.0055 · Cited by 148
‘Programming’ of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats
Franke, K., Harder, T., Aerts, L., Melchior, K., Fahrenkrog, S., Rodekamp, E., Ziska, T., Assche, F. A. V., Dudenhausen, J. W., & Plagemann, A. (2004) · Brain Research · doi:10.1016/j.brainres.2004.11.006 · Cited by 147
Neuropeptide Y, α-melanocyte–stimulating hormone, and monoamines in food intake regulation
Ramos, E. J. B., Meguid, M. M., Campos, A. C. L., & Coelho, J. C. U. (2005) · Nutrition · doi:10.1016/j.nut.2004.06.021 · Cited by 148
“, HS014, HS024, -MSH-[3-11], and HS028) timulates food intake [48,51,52], and MC4-R–deficient ice [53] and humans [54] have an obese phenotype.”
Background
THE CRITICAL ROLE OF THE MELANOCORTIN SYSTEM IN THE CONTROL OF ENERGY BALANCE
Seeley, R. J., Drazen, D. L., & Clegg, D. J. (2004) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.24.012003.132428 · Cited by 145
Opioid receptor involvement in the effect of AgRP- (83–132) on food intake and food selection
Hagan, M. M., Rushing, P. A., Benoit, S. C., Woods, S. C., & Seeley, R. J. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.280.3.r814 · Cited by 143
The Melanocortinergic Pathway Is Rapidly Recruited by Emotional Stress and Contributes to Stress-Induced Anorexia and Anxiety-Like Behavior
Liu, J., Garza, J. C., Truong, H. V., Henschel, J., Zhang, W., & Lu, X.-Y. (2007) · Endocrinology · doi:10.1210/en.2007-0745 · Cited by 141
Altered Expression of Agouti-Related Protein and Its Colocalization with Neuropeptide Y in the Arcuate Nucleus of the Hypothalamus during Lactation
Chen, P., Li, C., Haskell‐Luevano, C., Cone, R. D., & Smith, M. S. (1999) · Endocrinology · doi:10.1210/endo.140.6.6829 · Cited by 139
“It has been shown that AGRP exerts its function by binding to two of the receptors (MC3-R and MC4-R) for the POMC peptides (POMC) and preventing their activation by POMC peptides (10, 11, 22).”
Negative feedback regulation of hypophysiotropic thyrotropin-releasing hormone (TRH) synthesizing neurons: role of neuronal afferents and type 2 deiodinase
Fekete, C., & Lechan, R. M. (2007) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2007.04.002 · Cited by 137
“The arcuate nucleus contains at least two, distinct populations of neurons that are directly regulated by leptin [67;68;69;70;71], involved in the regulation of feeding behavior [71;72], and project to TRH neurons in the PVN [8;43;44;50].”
Background
Agouti-Related Protein (AGRP) Is Conserved and Regulated by Metabolic State in the Zebrafish, Danio rerio
Song, Y., Golling, G., Thacker, T. L., & Cone, R. D. (2003) · Endocrine · doi:10.1385/endo:22:3:257 · Cited by 137
Agouti and Agouti-related Protein: Analogies and Contrasts
Dinulescu, D. M., & Cone, R. D. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.10.6695 · Cited by 132
Agouti: from Mouse to Man, from Skin to Fat
Voisey, J., & van Daal, A. (2002) · Pigment Cell Research · doi:10.1034/j.1600-0749.2002.00039.x · Cited by 132
Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons – Implications for energy balance and glucose control
He, Z., Gao, Y., Lieu, L., Afrin, S., Cao, J., Michael, N. J., Dong, Y., Sun, J., Guo, H., & Williams, K. W. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.07.008 · Cited by 128
GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism
Wu, Q., & Palmiter, R. D. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.10.110 · Cited by 143
“Likewise, intracranial injection of AgRP has a long-lasting stimulatory effect on feeding and genetic over-expression of Agrp in the brain leads to obesity (Broberger and Hokfelt, 2001; Ollmann and Barsh, 1999; Rossi et al., 1998; Shutter et al., 1997).”
Background
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 HPT axis
Fekete, C., Sarkar, S., Rand, W. M., Harney, J. W., Emerson, C. H., Bianco, A. C., & Lechan, R. M. (2002) · Endocrinology · doi:10.1210/en.2002-220338 · Cited by 131
“AGRP acts as a competitive antagonist to-MSH at melanocortin receptors ( 12 ) and has both orexigenic and weight promoting properties (12).”
BackgroundInfluential
Signals that influence food intake and body weight
WOODS, S. (2005) · Physiology & Behavior · doi:10.1016/j.physbeh.2005.08.060 · Cited by 131

Authors: Rossi, M., Kim, M. S., Morgan, D. G. A., Small, C. J., Edwards, C. M. B., Sunter, D., Abusnana, S., Goldstone, A. P., Russell, S. H., Stanley, S. A., Smith, D. M., Yagaloff, K., Ghatei, M. A., & Bloom, S. R.
Affiliations: Hammersmith Hospital (GB)
ORCID: Abusnana, S.
Goldstone, A. P.
Stanley, S. A.
Smith, D. M.
Bloom, S. R.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 1998-10
Volume: 139
Issue: 10
Pages: 4428-4431
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/endo.139.10.6332
OpenAlex: W2171010063
Cited by: 576
References: 0
Citations by year: 2026: 2 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 9 · 2021: 11 · 2020: 7 · 2019: 16 · 2018: 8 · 2017: 13 · 2016: 16 · 2015: 15 · 2014: 16 · 2013: 22 · 2012: 29
FWCI: 11.74
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords: agouti-related protein, C-terminal fragment, alpha-melanocyte-stimulating hormone, melanocortin 3 receptor, melanocortin-4 receptor, dietary intake, hyperphagia, SHU9119, obesity, hypothalamus, cAMP signaling, intracerebroventricular administration
MeSH terms: alpha-MSH, Animals, Dose-Response Relationship, Drug, Eating, Injections, Intraventricular, Male, Peptide Fragments, Proteins, Rats, Wistar, Receptors, Corticotropin, Intercellular Signaling Peptides and Proteins, Receptor, Melanocortin, Type 3, Rats, Agouti Signaling Protein, Agouti-Related Protein

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A C-Terminal Fragment of Agouti-Related Protein Increases Feeding and Antagonizes the Effect of Alpha-Melanocyte Stimulating Hormone in Vivo

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