Fasting Induces a Large, Leptin-Dependent Increase in the Intrinsic Action Potential Frequency of Orexigenic Arcuate Nucleus Neuropeptide Y/Agouti-Related Protein Neurons
Abstract
The neuropeptide Y (NPY)/Agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus are thought to promote feeding. Here, we demonstrate that feeding state in vivo, through a leptin-dependent process, induces large and persistent changes in the electrophysiological activity of these neurons as measured extracellularly in vitro. Consistent with an orexigenic role, fasting induced a 4-fold increase in the basal action potential frequency of NPY/AgRP neurons. Leptin, when injected into fasted wild-type mice, induced a dose- and time-dependent decrease in spike frequency, which approached fed levels 2-3 h post treatment. In leptin-deficient (lep(ob)/lep(ob)) and leptin receptor-deficient (lepr(db)/lepr(db)) mice, NPY/AgRP spike frequency was not significantly increased by fasting, and even in mutant mice fed ad libitum, spike frequency was at least as high as in fasted wild-type mice. All recordings included GABA(A) and ionotropic glutamate receptor antagonists, suggesting that expression of this modulation is potentially intrinsic and not synaptically dependent. Recorded neurons were unambiguously identified using NPY-Sapphire transgenic mice. This is a remarkably straightforward example of a very robust in vitro electrophysiogical effect produced by a simple behavioral manipulation, food restriction.
Integrity signals
Registry
Cites
Statistics
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?
AgRP neurons are spontaneously active under control conditions.
“AgRP neurons are spontaneously active under control conditions [54].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [54]
Regulation of spontaneous firing of AgRP neurons can be achieved by synaptic and intrinsic mechanisms.
“Regulation of spontaneous firing of AgRP neurons can be achieved by synaptic and intrinsic mechanisms [54, 58–61].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [54]
Cites
Central nervous system control of food intake
Schwartz, M. W., Woods, S. C., Porte, D., Seeley, R. J., & Baskin, D. G. (2000) · Nature · doi:10.1038/35007534 · Cited by 6,451 · see citing works
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J., & Cone, R. D. (1997) · Nature · doi:10.1038/385165a0 · Cited by 1,902 · see citing works
Self-citationAntagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein
Ollmann, M. M., Wilson, B. D., Yang, Y.-K., Kerns, J. A., Chen, Y., Gantz, I., & Barsh, G. S. (1997) · Science · doi:10.1126/science.278.5335.135 · Cited by 1,881 · see citing works
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 1,219 · see citing works
Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons
Hahn, T. M., Breininger, J. F., Baskin, D. G., & Schwartz, M. W. (1998) · Nature Neuroscience · doi:10.1038/1082 · Cited by 1,164 · see citing works
Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor
Lu, D., Willard, D. H., Patel, I. R., Kadwell, S. H., Overton, L. K., Kost, T., Luther, M., Chen, W., Woychik, R. P., Wilkison, W. O., et al. (1994) · Nature · doi:10.1038/371799a0 · Cited by 1,075 · see citing works
Self-citationSTAT3 signalling is required for leptin regulation of energy balance but not reproduction
Bates, S. H., Stearns, W. H., Dundon, T. A., Schubert, M., Tso, A. W. K., Wang, Y., Banks, A. S., Lavery, H. J., Haq, A. K., Maratos-Flier, E., et al. (2003) · Nature · doi:10.1038/nature01388 · Cited by 1,010 · see citing works
Rapid Rewiring of Arcuate Nucleus Feeding Circuits by Leptin
Pinto, S., Roseberry, A. G., Liu, H., Diano, S., Shanabrough, M., Cai, X., Friedman, J. M., & Horvath, T. L. (2004) · Science · doi:10.1126/science.1089459 · Cited by 987 · see citing works
Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area
Elias, C. F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R. S., Bjorbæk, C., Flier, J. S., Saper, C. B., & Elmquist, J. K. (1999) · Neuron · doi:10.1016/s0896-6273(01)80035-0 · Cited by 924 · see citing works
Broberger, C., Johansen, J., Johansson, C., Schalling, M., & Hökfelt, T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.15043 · Cited by 798 · see citing works
Orexigenic 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 667 · see citing works
Hökfelt, T. G. M., Broberger, C., Xu, Q., Sergeyev, V., Ubink, R., & Diez, M. (2000) · Neuropharmacology · doi:10.1016/s0028-3908(00)00010-1 · Cited by 607 · see citing works
Inhibition of hypothalamic neuropeptide Y gene expression by insulin.
Schwartz, M. W., Sipols, A. J., Marks, J. L., Sanacora, G., White, J. D., Scheurink, A., Kahn, S. E., Baskin, D. G., Woods, S. C., & Figlewicz, D. P. (1992) · Endocrinology · doi:10.1210/endo.130.6.1597158 · Cited by 555 · see citing works
Mercer, J. G., Hoggard, N., Williams, L. M., Lawrence, C. B., Hannah, L. T., Morgan, P. J., & Trayhurn, P. (1996) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.1996.05161.x · Cited by 460 · see citing works
Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus
van den Top, M., Lee, K., Whyment, A. D., Blanks, A. M., & Spanswick, D. (2004) · Nature Neuroscience · doi:10.1038/nn1226 · Cited by 435 · see citing works
Genetic approaches to studying energy balance: perception and integration
Barsh, G. S., & Schwartz, M. W. (2002) · Nature Reviews Genetics · doi:10.1038/nrg862 · Cited by 417 · see citing works
Hagan, M. M., Rushing, P. A., Pritchard, L. M., Schwartz, M. W., Strack, A. M., der Ploeg, L. H. T. V., Woods, S. C., & Seeley, R. J. (2000) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.279.1.r47 · Cited by 320 · see citing works
Sanacora, G., Kershaw, M., Finkelstein, J. A., & White, J. D. (1990) · Endocrinology · doi:10.1210/endo-127-2-730 · Cited by 309 · see citing works
Leptin Regulation of Agrp and Npy mRNA in the Rat Hypothalamus
Körner, J., Savontaus, E., Chua, S. C., Leibel, R. L., & Wardlaw, S. L. (2001) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2001.00716.x · Cited by 213 · see citing works
Mizuno, T. M., Makimura, H., Silverstein, J. H., Roberts, J. L., Lopingco, T., & Mobbs, C. V. (1999) · Endocrinology · doi:10.1210/endo.140.10.6966 · Cited by 189 · see citing works
Role of glucocorticoids in mediating effects of fasting and diabetes on hypothalamic gene expression
Makimura, H., Mizuno, T. M., Isoda, F., Beasley, J., Silverstein, J. H., & Mobbs, C. V. (2003) · BMC Physiology · doi:10.1186/1472-6793-3-5 · Cited by 94 · see citing works
Chua, S. C., Brown, A. W., Kim, J.-H., Hennessey, K. L., Leibel, R. L., & Hirsch, J. (1991) · Molecular Brain Research · doi:10.1016/0169-328x(91)90038-y · Cited by 86 · see citing works
Shimizu‐Albergine, M., Ippolito, D. L., & Beavo, J. A. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-04-01238.2001 · Cited by 75 · see citing works
McNay, E. C., & Sherwin, R. S. (2003) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2003.08.014 · Cited by 74 · see citing works
van Heek, M., Mullins, D., Wirth, M., et al. (1996) · Hormone and Metabolic Research · doi:10.1055/s-2007-979872 · Cited by 50 · see citing works
Pharmacokinetics of human leptin in mice and rhesus monkeys
Åhrén, B., Baldwin, R. M., & Havel, P. J. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801447 · Cited by 44 · see citing works
The Anorexigenic Fatty Acid Synthase Inhibitor, C75, Is a Nonspecific Neuronal Activator
Takahashi, K. A., Smart, J. L., Liu, H., & Cone, R. D. (2003) · Endocrinology · doi:10.1210/en.2003-0337 · Cited by 42 · see citing works
Self-citation[9] Patch voltage clamping with low-resistance seals: Loose patch clamp
Roberts, W. M., & Almers, W. (1992) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(92)07011-c · Cited by 36 · see citing works
Horvat, S., & Bünger, L. (1999) · Laboratory Animals · doi:10.1258/002367799780487850 · Cited by 24 · see citing works
New method for genotyping the mouse Lep(ob) mutation, using a polymerase chain reaction assay.
Namae, M., Mori, Y., Yasuda, K., et al. (1998) · PubMed · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Anatomy and regulation of the central melanocortin system
Cone, R. D. (2005) · Nature Neuroscience · doi:10.1038/nn1455 · Cited by 1,583 · see citing works
Self-citationAGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training
Aponte, Y., Atasoy, D., & Sternson, S. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2739 · Cited by 1,157 · see citing works
Neurons for hunger and thirst transmit a negative-valence teaching signal
Betley, J. N., Xu, S., Cao, Z. F. H., Gong, R., Magnus, C. J., Yu, Y., & Sternson, S. M. (2015) · Nature · doi:10.1038/nature14416 · Cited by 704 · see citing works
Leptin and the endocrine control of energy balance
Friedman, J. M. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0095-y · Cited by 661 · see citing works
Studies on the Physiological Functions of the Melanocortin System
Cone, R. D. (2006) · Endocrine Reviews · doi:10.1210/er.2006-0034 · Cited by 615 · see citing works
Self-citationAn excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger
Krashes, M. J., Shah, B. P., Madara, J. C., Olson, D. P., Strochlic, D. E., Garfield, A. S., Vong, L., Pei, H., Watabe-Uchida, M., Uchida, N., et al. (2014) · Nature · doi:10.1038/nature12956 · Cited by 603 · see citing works
Dietrich, M. O., Liu, Z.-W., & Horvath, T. L. (2013) · Cell · doi:10.1016/j.cell.2013.09.004 · Cited by 306 · see citing works
Hunger-Driven Motivational State Competition
Burnett, C. J., Li, C., Webber, E., Tsaousidou, E., Xue, S. Y., Brüning, J. C., & Krashes, M. J. (2016) · Neuron · doi:10.1016/j.neuron.2016.08.032 · Cited by 305 · see citing works
Liu, T., Kong, D., Shah, B. P., Ye, C., Koda, S., Saunders, A., Ding, J. B., Yang, Z., Sabatini, B. L., & Lowell, B. B. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.027 · Cited by 296 · see citing works
Coppola, A., Liu, Z.-W., Andrews, Z. B., Paradis, E., Roy, M.-C., Friedman, J. M., Ricquier, D., Richard, D., Horvath, T. L., Gao, X.-B., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2006.12.002 · Cited by 295 · see citing works
HypoMap—a unified single-cell gene expression atlas of the murine hypothalamus
Steuernagel, L., Lam, B. Y. H., Klemm, P., Dowsett, G. K. C., Bauder, C. A., Tadross, J. A., Hitschfeld, T. S., del Rio Martin, A., Chen, W., de Solis, A. J., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00657-y · Cited by 267 · see citing works
Hypothalamic control of energy balance: insights into the role of synaptic plasticity
Dietrich, M. O., & Horvath, T. L. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.12.005 · Cited by 227 · see citing works
Baver, S. B., Hope, K., Guyot, S., Bjørbaek, C., Kaczorowski, C., & O'Connell, K. M. S. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.4861-12.2014 · Cited by 203 · see citing works
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 · see citing works
Brain Adipocytokine Action and Metabolic Regulation
Ahima, R. S., Qi, Y., Singhal, N. S., Jackson, M. B., & Scherer, P. E. (2006) · Diabetes · doi:10.2337/db06-s018 · Cited by 150 · see citing works
Synaptic plasticity in neuronal circuits regulating energy balance
Zeltser, L. M., Seeley, R. J., & Tschöp, M. H. (2012) · Nature Neuroscience · doi:10.1038/nn.3219 · Cited by 147 · see citing works
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 · see citing works
Hunger and Satiety Gauge Reward Sensitivity
Cassidy, R. M., & Tong, Q. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00104 · Cited by 93 · see citing works
Fang, X., Jiang, S., Wang, J., Bai, Y., Kim, C. S., Blake, D., Weintraub, N. L., Lei, Y., & Lu, X.-Y. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-01004-x · Cited by 95 · see citing works
Dong, Y., Carty, J., Goldstein, N., He, Z., Hwang, E., Chau, D., Wallace, B., Kabahizi, A., Lieu, L., Peng, Y., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101352 · Cited by 93 · see citing works
Brain control of energy homeostasis: implications for anti-obesity pharmacotherapy
Johansen, V. B. I., Petersen, J., Lund, J., Mathiesen, C. V., Fenselau, H., & Clemmensen, C. (2025) · Cell · doi:10.1016/j.cell.2025.06.010 · Cited by 53 · see citing works
Ghidewon, M., Wald, H. S., McKnight, A. D., De Jonghe, B. C., Breen, D. M., Alhadeff, A. L., Borner, T., & Grill, H. J. (2022) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14663 · Cited by 51 · see citing works
The hormonal signature of energy deficit: Increasing the value of food reward
Lockie, S. H., & Andrews, Z. B. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.08.003 · Cited by 50 · see citing works
A Small Potassium Current in AgRP/NPY Neurons Regulates Feeding Behavior and Energy Metabolism
He, Y., Shu, G., Yang, Y., Xu, P., Xia, Y., Wang, C., Saito, K., Hinton, A., Yan, X., Liu, C., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.044 · Cited by 34 · see citing works
Competition between stochastic neuropeptide signals calibrates the rate of satiation
Zhang, S. X., Kim, A., Madara, J. C., Zhu, P. K., Christenson, L. F., Lutas, A., Kalugin, P. N., Jin, Y., Pal, A., Tian, L., et al. (2023) · doi:10.1101/2023.07.11.548551 · Cited by 56 · see citing works
- Authors
- Takahashi, K. A., & Cone, R. D.
- Affiliations
- Albert Einstein College of Medicine (US)
- Oregon Health & Science University (US)
- Corresponding author
- Takahashi, Kanji A.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-03
- Volume
- 146
- Issue
- 3
- Pages
- 1043-1047
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2127818104
- Cited by
- 308
- References
- 30
- Citations by year
- 2026: 4 · 2025: 18 · 2024: 22 · 2023: 15 · 2022: 20 · 2021: 29 · 2020: 19 · 2019: 13 · 2018: 13 · 2017: 21 · 2016: 18 · 2015: 19 · 2014: 8 · 2013: 11 · 2012: 14
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK051730, DK51730)
- 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
- fasting, leptin, neuropeptide Y, agouti-related protein, arcuate nucleus, orexigenic neurons, action potential frequency, hypothalamic neurons, feeding behavior, leptin receptor deficiency, leptin deficiency, intrinsic excitability
- MeSH terms
- Action Potentials, Animals, Arcuate Nucleus of Hypothalamus, Dose-Response Relationship, Drug, Electrophysiology, Food Deprivation, Hydrogen-Ion Concentration, Mice, Inbred CBA, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropeptide Y, Proteins, Time Factors, Leptin, Intercellular Signaling Peptides and Proteins, Mice, Agouti-Related Protein
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
