help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wilson, B. D.
Right arrow Articles by Barsh, G. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilson, B. D.
Right arrow Articles by Barsh, G. S.
Endocrinology Vol. 140, No. 5 2387-2397
Copyright © 1999 by The Endocrine Society

ARTICLES

Physiological and Anatomical Circuitry between Agouti-Related Protein and Leptin Signaling1

Brent D. Wilson2, Didier Bagnol2, Christopher B. Kaelin, Michael M. Ollmann3, Ira Gantz, Stanley J. Watson and Gregory S. Barsh4

Departments of Pediatrics and Genetics and the Howard Hughes Medical Institute, Stanford University School of Medicine (B.D.W., C.B.K., M.M.O., G.S.B.), Stanford, California 94305-5428; the Mental Health Research Institute (D.B., S.J.W.) and the Department of Surgery (I.G.), University of Michigan School of Medicine, Ann Arbor, Michigan 48109-0682

Address all correspondence and requests for reprints to: Dr. Greg Barsh, Beckman Center B271A, Stanford University School of Medicine, Stanford, California 94305-5323. E-mail: gbarsh{at}cmgm.stanford.edu

Agouti-related protein (AGRP) is an orexigenic neuropeptide that acts via central melanocortin receptors, and whose messenger RNA (mRNA) levels are elevated in leptin-deficient mice. Fasting associated with a decline in circulating leptin normally causes a 15-fold elevation of hypothalamic Agrp mRNA levels but has no effect in leptin-deficient mice. Chronic hyperleptinemia associated with the tubby and Cpefat mutations has no effect on Agrp mRNA levels, but short term leptin administration causes a 17% reduction of Agrp mRNA levels in nonmutant mice and a 700% reduction in leptin-deficient mice. In young nonobese animals, melanocortin receptor blockade associated with the Ay mutation causes complete resistance to leptin-induced weight loss. Dual in situ hybridization reveals that Agrp-expressing neurons in the medial portion of the arcuate nucleus constitute a subpopulation different from Pomc-expressing neurons, and that a significant proportion of Agrp-expressing neurons (10–25%) coexpresses the leptin receptor, Lepr-b. Immunocytochemistry confirms distinct locations of AGRP- and POMC-expressing cell bodies, but reveals an overlapping distribution of their terminal fields in the arcuate nucleus, the paraventricular hypothalamus, and the dorsomedial hypothalamus. These results suggest that in the fed state, AGRP is normally suppressed by leptin, and that release of this suppression during fasting leads to increased ingestive behavior.




This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. J. Barnes, S. D. Primeaux, and G. A. Bray
Food deprivation increases the mRNA expression of {micro}-opioid receptors in the ventral medial hypothalamus and arcuate nucleus
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1385 - R1390.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
N. C. Bingham, K. K. Anderson, A. L. Reuter, N. R. Stallings, and K. L. Parker
Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome
Endocrinology, May 1, 2008; 149(5): 2138 - 2148.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
G. Li, Y. Zhang, E. Rodrigues, D. Zheng, M. Matheny, K.-Y. Cheng, and P. J. Scarpace
Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss
Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E252 - E258.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
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]

Home page
 Mol. Endocrinol.Home page
C. B. Kaelin, L. Gong, A. W. Xu, F. Yao, K. Hockman, G. J. Morton, M. W. Schwartz, G. S. Barsh, and R. G. MacKenzie
Signal Transducer and Activator of Transcription (Stat) Binding Sites But Not Stat3 Are Required for Fasting-Induced Transcription of Agouti-Related Protein Messenger Ribonucleic Acid
Mol. Endocrinol., October 1, 2006; 20(10): 2591 - 2602.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
T. Tsubone, T. Masaki, I. Katsuragi, K. Tanaka, T. Kakuma, and H. Yoshimatsu
Leptin downregulates ghrelin levels in streptozotocin-induced diabetic mice
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1703 - R1706.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
Y. Zhang, G. E Kilroy, T. M. Henagan, V. Prpic-Uhing, W. G. Richards, A. W. Bannon, R. L. Mynatt, and T. W. Gettys
Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin
FASEB J, September 1, 2005; 19(11): 1482 - 1491.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
M. J H Kas, A. W Bruijnzeel, J. R Haanstra, V. M Wiegant, and R. A H Adan
Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event
J. Mol. Endocrinol., August 1, 2005; 35(1): 159 - 164.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
Z A Archer, S M Rhind, P A Findlay, C E Kyle, M C Barber, and C L Adam
Hypothalamic responses to peripheral glucose infusion in food-restricted sheep are influenced by photoperiod
J. Endocrinol., March 1, 2005; 184(3): 515 - 525.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
S. Sakurai, T. Nishijima, S. Takahashi, K. Yamauchi, Z. Arihara, and K. Takahashi
Low Plasma Orexin-A Levels Were Improved by Continuous Positive Airway Pressure Treatment in Patients With Severe Obstructive Sleep Apnea-Hypopnea Syndrome
Chest, March 1, 2005; 127(3): 731 - 737.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. Bugarith, T. T. Dinh, A.-J. Li, R. C. Speth, and S. Ritter
Basomedial Hypothalamic Injections of Neuropeptide Y Conjugated to Saporin Selectively Disrupt Hypothalamic Controls of Food Intake
Endocrinology, March 1, 2005; 146(3): 1179 - 1191.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. B. Kaelin, A. W. Xu, X.-Y. Lu, and G. S. Barsh
Transcriptional Regulation of Agouti-Related Protein (Agrp) in Transgenic Mice
Endocrinology, December 1, 2004; 145(12): 5798 - 5806.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
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]

Home page
 EndocrinologyHome page
S. R. Ladyman and D. R. Grattan
Region-Specific Reduction in Leptin-Induced Phosphorylation of Signal Transducer and Activator of Transcription-3 (STAT3) in the Rat Hypothalamus Is Associated with Leptin Resistance during Pregnancy
Endocrinology, August 1, 2004; 145(8): 3704 - 3711.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
F. Maekawa, H.-M. A. Quah, K. Tanaka, and H. Ohki-Hamazaki
Leptin Resistance and Enhancement of Feeding Facilitation by Melanin-Concentrating Hormone in Mice Lacking Bombesin Receptor Subtype-3
Diabetes, March 1, 2004; 53(3): 570 - 576.
[Abstract] [Full Text] [PDF]

Home page
 Recent Prog Horm ResHome page
K. L.J. Ellacott and R. D. Cone
The Central Melanocortin System and the Integration of Short- and Long-term Regulators of Energy Homeostasis
Recent Prog. Horm. Res., January 1, 2004; 59(1): 395 - 408.
[Abstract] [Full Text]

Home page
 DiabetesHome page
D. L. Drazen, M. D. Wortman, M. W. Schwartz, D. J. Clegg, G. van Dijk, S. C. Woods, and R. J. Seeley
Adrenalectomy Alters the Sensitivity of the Central Nervous System Melanocortin System
Diabetes, December 1, 2003; 52(12): 2928 - 2934.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. R. Hansen, S. M. Krasnow, M. A. Nolan, G. S. Fraley, J. W. Baumgartner, D. K. Clifton, and R. A. Steiner
Activation of the Sympathetic Nervous System by Galanin-Like Peptide--A Possible Link between Leptin and Metabolism
Endocrinology, November 1, 2003; 144(11): 4709 - 4717.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
X.-Y. Lu, G. S. Barsh, H. Akil, and S. J. Watson
Interaction between {alpha}-Melanocyte-Stimulating Hormone and Corticotropin-Releasing Hormone in the Regulation of Feeding and Hypothalamo-Pituitary-Adrenal Responses
J. Neurosci., August 27, 2003; 23(21): 7863 - 7872.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
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]

Home page
 EndocrinologyHome page
E. Xiao, L. Xia-Zhang, N. R. Vulliemoz, M. Ferin, and S. L. Wardlaw
Agouti-Related Protein Stimulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis and Enhances the HPA Response to Interleukin-1 in the Primate
Endocrinology, May 1, 2003; 144(5): 1736 - 1741.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
V. Prpic, P. M. Watson, I. C. Frampton, M. A. Sabol, G. E. Jezek, and T. W. Gettys
Differential Mechanisms and Development of Leptin Resistance in A/J Versus C57BL/6J Mice during Diet-Induced Obesity
Endocrinology, April 1, 2003; 144(4): 1155 - 1163.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
S. M. Krasnow, G. S. Fraley, S. M. Schuh, J. W. Baumgartner, D. K. Clifton, and R. A. Steiner
A Role for Galanin-Like Peptide in the Integration of Feeding, Body Weight Regulation, and Reproduction in the Mouse
Endocrinology, March 1, 2003; 144(3): 813 - 822.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
I. Gantz and T. M. Fong
The melanocortin system
Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E468 - E474.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
I. J. Clarke, A. Rao, Y. Chilliard, C. Delavaud, and G. A. Lincoln
Photoperiod effects on gene expression for hypothalamic appetite-regulating peptides and food intake in the ram
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R101 - R115.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
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]

Home page
 J. Clin. Endocrinol. Metab.Home page
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]

Home page
 EndocrinologyHome page
H. C. Chen, Z. Ladha, and R. V. Farese Jr.
Deficiency of Acyl Coenzyme A:Diacylglycerol Acyltransferase 1 Increases Leptin Sensitivity in Murine Obesity Models
Endocrinology, August 1, 2002; 143(8): 2893 - 2898.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. Qian, H. Chen, D. Weingarth, M. E. Trumbauer, D. E. Novi, X. Guan, H. Yu, Z. Shen, Y. Feng, E. Frazier, et al.
Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice
Mol. Cell. Biol., July 15, 2002; 22(14): 5027 - 5035.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
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]

Home page
 EndocrinologyHome page
K. L. J. Ellacott, C. B. Lawrence, N. J. Rothwell, and S. M. Luckman
PRL-Releasing Peptide Interacts with Leptin to Reduce Food Intake and Body Weight
Endocrinology, February 1, 2002; 143(2): 368 - 374.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
H. J. Grill, M. W. Schwartz, J. M. Kaplan, J. S. Foxhall, J. Breininger, and D. G. Baskin
Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake
Endocrinology, January 1, 2002; 143(1): 239 - 246.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. J. Hwa, L. Ghibaudi, J. Gao, and E. M. Parker
Central melanocortin system modulates energy intake and expenditure of obese and lean Zucker rats
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2001; 281(2): R444 - R451.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. Fekete, J. Kelly, E. Mihaly, S. Sarkar, W. M. Rand, G. Legradi, C. H. Emerson, and R. M. Lechan
Neuropeptide Y Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid Axis
Endocrinology, June 1, 2001; 142(6): 2606 - 2613.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
S. L. Wardlaw
Obesity as a Neuroendocrine Disease: Lessons to Be Learned from Proopiomelanocortin and Melanocortin Receptor Mutations in Mice and Men
J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1442 - 1446.
[Full Text]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
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]

Home page
 DiabetesHome page
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]

Home page
 Mol. Endocrinol.Home page
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]

Home page
 J. Nutr.Home page
M. Jang, A. Mistry, A. G. Swick, and D. R. Romsos
Leptin Rapidly Inhibits Hypothalamic Neuropeptide Y Secretion and Stimulates Corticotropin-Releasing Hormone Secretion in Adrenalectomized Mice
J. Nutr., November 1, 2000; 130(11): 2813 - 2820.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. E. McMinn, C. W. Wilkinson, P. J. Havel, S. C. Woods, and M. W. Schwartz
Effect of intracerebroventricular alpha -MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R695 - R703.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Korner, S. L. Wardlaw, S.-M. Liu, I. M. Conwell, R. L. Leibel, and S. C. Chua Jr.
Effects of Leptin Receptor Mutation on Agrp Gene Expression in Fed and Fasted Lean and Obese (LA/N-faf) Rats
Endocrinology, July 1, 2000; 141(7): 2465 - 2471.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. M. Hagan, P. A. Rushing, L. M. Pritchard, M. W. Schwartz, A. M. Strack, L. H. T. Van der Ploeg, S. C. Woods, and R. J. Seeley
Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2000; 279(1): R47 - R52.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J.-Y. Li, S. Finniss, Y.-K. Yang, Q. Zeng, S.-Y. Qu, G. Barsh, C. Dickinson, and I. Gantz
Agouti-Related Protein-Like Immunoreactivity: Characterization of Release from Hypothalamic Tissue and Presence in Serum
Endocrinology, June 1, 2000; 141(6): 1942 - 1950.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. C. Benoit, M. W. Schwartz, J. L. Lachey, M. M. Hagan, P. A. Rushing, K. A. Blake, K. A. Yagaloff, G. Kurylko, L. Franco, W. Danhoo, et al.
A Novel Selective Melanocortin-4 Receptor Agonist Reduces Food Intake in Rats and Mice without Producing Aversive Consequences
J. Neurosci., May 1, 2000; 20(9): 3442 - 3448.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. G. Hohmann, T. H. Teal, D. K. Clifton, J. Davis, V. J. Hruby, G. Han, and R. A. Steiner
Differential role of melanocortins in mediating leptin's central effects on feeding and reproduction
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R50 - R59.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
D. Bagnol, X.-Y. Lu, C. B. Kaelin, H. E. W. Day, M. Ollmann, I. Gantz, H. Akil, G. S. Barsh, and S. J. Watson
Anatomy of an Endogenous Antagonist: Relationship between Agouti-Related Protein and Proopiomelanocortin in Brain
J. Neurosci., September 15, 1999; 19(18): RC26 - RC26.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1999 by The Endocrine Society