The DOI matches its Crossref record; 56 of the 57 references it cites were found in a registry or an index.
Diet-Induced Obesity Causes Ghrelin Resistance in Arcuate NPY/AgRP Neurons
Abstract
Circulating ghrelin is decreased in obesity, and peripheral ghrelin does not induce food intake in obese mice. We investigated whether ghrelin resistance was a centrally mediated phenomenon involving dysregulated neuropeptide Y (NPY) and agouti-related peptide (AgRP) circuits. We show that diet-induced obesity (DIO) (12 wk) suppresses the neuroendocrine ghrelin system by decreasing acylated and total plasma ghrelin, decreasing ghrelin and Goat mRNA in the stomach, and decreasing expression of hypothalamic GHSR. Peripheral (ip) or central (intracerebroventricular) ghrelin injection was able to induce food intake and arcuate nucleus Fos immunoreactivity in chow-fed but not high-fat diet-fed mice. DIO decreased expression of Npy and Agrp mRNA, and central ghrelin was unable to promote expression of these genes. Ghrelin did not induce AgRP or NPY secretion in hypothalamic explants from DIO mice. Injection of NPY intracerebroventricularly increased food intake in both chow-fed and high-fat diet-fed mice, indicating that downstream NPY/AgRP neural targets are intact and that defective NPY/AgRP function is a primary cause of ghrelin resistance. Ghrelin resistance in DIO is not confined to the NPY/AgRP neurons, because ghrelin did not stimulate growth hormone secretion in DIO mice. Collectively, our data suggests that DIO causes ghrelin resistance by reducing NPY/AgRP responsiveness to plasma ghrelin and suppressing the neuroendocrine ghrelin axis to limit further food intake. Ghrelin has a number of functions in the brain aside from appetite control, including cognitive function, mood regulation, and protecting against neurodegenerative diseases. Thus, central ghrelin resistance may potentiate obesity-related cognitive decline, and restoring ghrelin sensitivity may provide therapeutic outcomes for maintaining healthy aging.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Indeed, ghrelin has lower orexigenic activity in DIO rodents due to a reduction in activation and plasticity of NPY/AgRP neurons 138.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [138]
Citations
Cites
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859
Ghrelin is a growth-hormone-releasing acylated peptide from stomach
Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., & Kangawa, K. (1999) · Nature · doi:10.1038/45230 · Cited by 8,479
Ghrelin induces adiposity in rodents
Tschöp, M., Smiley, D. L., & Heiman, M. L. (2000) · Nature · doi:10.1038/35038090 · Cited by 3,949
A role for ghrelin in the central regulation of feeding
Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., & Matsukura, S. (2001) · Nature · doi:10.1038/35051587 · Cited by 3,443
A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans
Cummings, D. E., Purnell, J. Q., Frayo, R. S., Schmidova, K., Wisse, B. E., & Weigle, D. S. (2001) · Diabetes · doi:10.2337/diabetes.50.8.1714 · Cited by 2,940
A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release
Howard, A., Feighner, S., Cully, D., Arena, J. P., Liberator, P., Rosenblum, C., Hamelin, M., Hreniuk, D. L., Palyha, O., Anderson, J., et al. (1996) · Science · doi:10.1126/science.273.5277.974 · Cited by 2,106
Circulating Ghrelin Levels Are Decreased in Human Obesity
Tschöp, M. H., Weyer, C., Tataranni, P. A., Devanarayan, V., Ravussin, É., & Heiman, M. L. (2001) · Diabetes · doi:10.2337/diabetes.50.4.707 · Cited by 2,031
Cowley, M. A., Smith, R. G., Diano, S., Tschöp, M., Pronchuk, N., Grove, K. L., Strasburger, C. J., Bidlingmaier, M., Esterman, M., Heiman, M. L., et al. (2003) · Neuron · doi:10.1016/s0896-6273(03)00063-1 · Cited by 1,679
Self-citationHigh-Fat Diet Disrupts Behavioral and Molecular Circadian Rhythms in Mice
Kohsaka, A., Laposky, A. D., Ramsey, K. M., Estrada, C., Joshu, C., Kobayashi, Y., Turek, F. W., & Bass, J. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.09.006 · Cited by 1,528
Trophic Action of Leptin on Hypothalamic Neurons That Regulate Feeding
Bouret, S. G., Draper, S. J., & Simerly, R. B. (2004) · Science · doi:10.1126/science.1095004 · Cited by 1,247
Yang, J. H., Brown, M. S., Liang, G., Grishin, N. V., & Goldstein, J. L. (2008) · Cell · doi:10.1016/j.cell.2008.01.017 · Cited by 1,207
Expression of ghrelin receptor mRNA in the rat and the mouse brain
Zigman, J. M., Jones, J. E., Lee, C. E., Saper, C. B., & Elmquist, J. K. (2006) · The Journal of Comparative Neurology · doi:10.1002/cne.20823 · Cited by 1,074
Abizaid, A., Liu, Z.-W., Andrews, Z. B., Shanabrough, M., Borok, E., Elsworth, J. D., Roth, R. H., Sleeman, M. W., Picciotto, M. R., Tschöp, M. H., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29867 · Cited by 984
Self-citationGhrelin controls hippocampal spine synapse density and memory performance
Diano, S., Farr, S. A., Benoit, S. C., McNay, E. C., da Silva, I., Horvath, B., Gaskin, F. S., Nonaka, N., Jaeger, L. B., Banks, W. A., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1656 · Cited by 828
UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals
Andrews, Z. B., Liu, Z.-W., Walllingford, N., Erion, D. M., Borok, E., Friedman, J. M., Tschöp, M. H., Shanabrough, M., Cline, G., Shulman, G. I., et al. (2008) · Nature · doi:10.1038/nature07181 · Cited by 710
Self-citationOrexigenic Action of Peripheral Ghrelin Is Mediated by Neuropeptide Y and Agouti-Related Protein
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., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1596 · Cited by 685
The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress
Lutter, M., Sakata, I., Osborne-Lawrence, S., Rovinsky, S. A., Anderson, J. G., Jung, S., Birnbaum, S., Yanagisawa, M., Elmquist, J. K., Nestler, E. J., et al. (2008) · Nature Neuroscience · doi:10.1038/nn.2139 · Cited by 644
Kamegai, J., Tamura, H., Shimizu, T., Ishii, S., Sugihara, H., & Wakabayashi, I. (2001) · Diabetes · doi:10.2337/diabetes.50.11.2438 · Cited by 624
Cognitive impairment following high fat diet consumption is associated with brain inflammation
Pistell, P. J., Morrison, C. D., Gupta, S., Knight, A. G., Keller, J. N., Ingram, D. K., & Bruce‐Keller, A. J. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.11.010 · Cited by 623
Willesen, M. G., Kristensen, P., & Rømer, J. (1999) · Neuroendocrinology · doi:10.1159/000054491 · Cited by 605
Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons
Enriori, P. J., Evans, A. E., Sinnayah, P., Jobst, E. E., Tonelli-Lemos, L., Billes, S. K., Glavas, M. M., Grayson, B. E., Perello, M., Nillni, E. A., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.02.004 · Cited by 552
Self-citationHigh constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist
Holst, B., Cygankiewicz, A., Jensen, T. H., Ankersen, M., & Schwartz, T. W. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0069 · Cited by 515
Horváth, T. L., Diano, S., & van den Pol, A. N. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-03-01072.1999 · Cited by 508
Obesity effects on depression: systematic review of epidemiological studies
Atlantis, E., & Baker, M. (2008) · International Journal of Obesity · doi:10.1038/ijo.2008.54 · Cited by 399
Kamegai, J., Tamura, H., Shimizu, T., Ishii, S., Sugihara, H., & Wakabayashi, I. (2000) · Endocrinology · doi:10.1210/endo.141.12.7920 · Cited by 379
Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature
Pantel, J. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25303 · Cited by 364
Hewson, A. K., & Dickson, S. L. (2000) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2000.00584.x · Cited by 359
Wang, L., Saint-Pierre, D. H., & Taché, Y. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00241-0 · Cited by 334
Sabia, S., Mika Kivimaki, B., Shipley, M. J., Marmot, M. G., & Singh‐Manoux, A. (2008) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26482 · Cited by 298
Andrews, Z. B., Erion, D., Beiler, R., Liu, Z.-W., Abizaid, A., Zigman, J., Elsworth, J. D., Savitt, J. M., DiMarchi, R., Tschöp, M., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3890-09.2009 · Cited by 289
Self-citationHypothalamic Neural Projections Are Permanently Disrupted in Diet-Induced Obese Rats
Bouret, S. G., Gorski, J. N., Patterson, C. M., Chen, S. H., Levin, B. E., & Simerly, R. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.12.001 · Cited by 252
Shuto, Y., Shibasaki, T., Otagiri, A., Kuriyama, H., Ohata, H., Tamura, H., Kamegai, J., Sugihara, H., Oikawa, S., & Wakabayashi, I. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0213300 · Cited by 220
Association between weight perception and psychological distress
Atlantis, E. E., & Ball, K. (2007) · International Journal of Obesity · doi:10.1038/sj.ijo.0803762 · Cited by 193
Meal Pattern Analysis of Diet‐Induced Obesity in Susceptible and Resistant Rats
Farley, C., Cook, J. A., Spar, B. D., Austin, T. M., & Kowalski, T. J. (2003) · Obesity Research · doi:10.1038/oby.2003.116 · Cited by 183
New Insights into the Mechanisms of Macroautophagy in Mammalian Cells
Eskelinen, E. (2008) · International review of cytology · doi:10.1016/s1937-6448(07)66005-5 · Cited by 161
Banks, W., Burney, B. O., & Robinson, S. (2008) · Peptides · doi:10.1016/j.peptides.2008.07.001 · Cited by 155
Vogelzangs, N., Kritchevsky, S. B., Beekman, A. T. F., Brenes, G. A., Newman, A. B., Satterfield, S., Yaffe, K., Harris, T. B., Penninx, B. W. J. H., & Study, H. A. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.08m04743blu · Cited by 155
Fasting plasma ghrelin levels in subtypes of anorexia nervosa
Tanaka, M., Naruo, T., Yasuhara, D., Tatebe, Y., Nagai, N., Shiiya, T., Nakazato, M., Matsukura, S., & Nozoe, S.-I. (2003) · Psychoneuroendocrinology · doi:10.1016/s0306-4530(02)00066-5 · Cited by 143
Légrádi, G., & Lechan, R. M. (1998) · Endocrinology · doi:10.1210/endo.139.7.6113 · Cited by 138
Dahl, A., Hassing, L. B., Fransson, E. I., Berg, S., Gatz, M., Reynolds, C. A., & Pedersen, N. L. (2009) · The Journals of Gerontology Series A · doi:10.1093/gerona/glp035 · Cited by 138
Perreault, M., Istrate, N., Wang, L., Nichols, A., Tozzo, E., & Stricker‐Krongrad, A. (2004) · International Journal of Obesity · doi:10.1038/sj.ijo.0802640 · Cited by 132
Ghrelin stimulates neurogenesis in the dorsal motor nucleus of the vagus
Zhang, W., Lin, T. R.-Y., Hu, Y., Fan, Y., Zhao, L., Stuenkel, E. L., & Mulholland, M. W. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.064121 · Cited by 125
Barazzoni, R., Zanetti, M., Stebel, M., Biolo, G., Cattin, L., & Guarnieri, G. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00281-6 · Cited by 124
In vivo characterization of high Basal signaling from the ghrelin receptor
Petersen, P. S., Woldbye, D. P. D., Madsen, A. N., Egerod, K. L., Jin, C., Lang, M., Rasmussen, M., Beck-Sickinger, A. G., & Holst, B. (2009) · Endocrinology · doi:10.1210/en.2008-1638 · Cited by 121
Ghrelin Main Action on the Regulation of Growth Hormone Release Is Exerted at Hypothalamic Level
POPOVIC, V. M., Miljić, D., Micić, D., Damjanovic, S. S., Arvat, E., Ghigo, E., Diéguez, C., & Casanueva, F. F. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030211 · Cited by 117
Sucrose-induced obesity impairs novel object recognition learning in young rats
Jurdak, N. A., & Kanarek, R. B. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2008.07.023 · Cited by 110
Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus
Osterstock, G., Escobar, P., Mitutsova, V., Gouty‐Colomer, L., Fontanaud, P., Molino, F., Fehrentz, J., Carmignac, D. F., Martínez, J., Guérineau, N. C., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009159 · Cited by 82
TONI, R., JACKSON, I. M. D., & LECHAN, R. M. (1990) · Endocrinology · doi:10.1210/endo-126-5-2444 · Cited by 82
Uncoupling Protein-2 Decreases the Lipogenic Actions of Ghrelin
Andrews, Z. B., Erion, D. M., Beiler, R. J., Choi, C. S., Shulman, G. I., & Horváth, T. L. (2010) · Endocrinology · doi:10.1210/en.2009-0850 · Cited by 48
Self-citationThe hyperphagic effect of ghrelin is inhibited in mice by a diet high in fat.
Gardiner, J., Campbell, D., Patterson, M., Kent, A., Ghatei, M., Bloom, S., & Bewick, G. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.02.012 · Cited by 44
Effect of reducing hypothalamic ghrelin receptor gene expression on energy balance
Shrestha, Y. B., Wickwire, K., & Giraudo, S. Q. (2009) · Peptides · doi:10.1016/j.peptides.2009.03.013 · Cited by 40
Regulation of neuropeptide Y release from hypothalamic slices by melanocortin-4 agonists and leptin
King, P., Widdowson, P. S., Doods, H. N., & Williams, G. (2000) · Peptides · doi:10.1016/s0196-9781(99)00168-0 · Cited by 27
Blunted Fasting-Induced Hypothalamic Activation and Refeeding Hyperphagia in Late-Onset Obesity
Becskei, C., Lutz, T. A., & Riediger, T. (2009) · Neuroendocrinology · doi:10.1159/000251723 · Cited by 22
Blunted metabolic response to fasting in obese mice
Ueno, N., Asakawa, A., & Inui, A. (2007) · Endocrine · doi:10.1007/s12020-007-9016-z · Cited by 21
Gene expression in hypothalamus and brown adipose tissue of mice divergently selected for heat loss
Allan, M. F., Nielsen, M. K., & Pomp, D. (2000) · Physiological Genomics · doi:10.1152/physiolgenomics.2000.3.3.149 · Cited by 18
Psychosocial Predictors, Higher Body Mass Index, and Aspects of Neurocognitive Dysfunction
Brook, J. S., Zhang, C., Saar, N. S., & Brook, D. W. (2009) · Perceptual and Motor Skills · doi:10.2466/pms.108.1.181-195 · Cited by 17
Cited by
Sorted by citations
Müller, T. D., Nogueiras, R., Andermann, M. L., Andrews, Z. B., Anker, S. D., Argente, J., Batterham, R. L., Benoit, S. C., Bowers, C. Y., Broglio, F., et al. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.03.005 · Cited by 1,034
Self-citationHypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity
Timper, K., & Brüning, J. C. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.026609 · Cited by 851
Schneeberger, M., Everard, A., Gómez-Valadés, A. G., Matamoros, S., Ramírez, S., Delzenne, N. M., Gomis, R., Claret, M., & Cani, P. D. (2015) · Scientific Reports · doi:10.1038/srep16643 · Cited by 798
Hypothalamic Tanycytes Are an ERK-Gated Conduit for Leptin into the Brain
Balland, É., Dam, J., Langlet, F., Caron, É., Steculorum, S. M., Messina, A., Rasika, S., Falluel‐Morel, A., Anouar, Y., Dehouck, B., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.12.015 · Cited by 535
The cellular and molecular bases of leptin and ghrelin resistance in obesity
Cui, H., López, M., & Rahmouni, K. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.222 · Cited by 498
Metadata
- Authors
- Briggs, D. I., Enriori, P. J., Lemus, M. B., Cowley, M. A., & Andrews, Z. B.
- Affiliations
- Monash University (AU)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2010-09-08
- Volume
- 151
- Issue
- 10
- Pages
- 4745-4755
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2143711558
- Cited by
- 320
- References
- 57
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 15 · 2023: 18 · 2022: 15 · 2021: 20 · 2020: 22 · 2019: 19 · 2018: 13 · 2017: 22 · 2016: 18 · 2015: 30 · 2014: 25 · 2013: 20 · 2012: 27
- FWCI
- 10.02
- 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
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- ghrelin resistance, diet-induced obesity, neuropeptide Y, agouti-related protein, arcuate nucleus, hypothalamic neurons, growth hormone secretagogue receptor, food intake regulation, growth hormone secretion, high-fat diet, ghrelin signaling
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Cognition, Diet, Atherogenic, Drug Resistance, Eating, Goats, Male, Mice, Inbred C57BL, Mice, Obese, Neurons, Neuropeptide Y, Obesity, Growth Hormone, Mice, Agouti-Related Protein, Ghrelin
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
