Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus
Open accessAbstract
The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.
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Leptin rapidly changes the membrane potential and firing rate of hypothalamic neurons in electrophysiological studies.
“in electrophysiological studies using freshly prepared hypothalamic slices, leptin rapidly changes the membrane potential and firing rate of neurons (42, 176)”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [42]
Leptin inhibits the firing rate of NPY/AgRP neurons, depolarizes POMC neurons, and activates PI3K signaling in POMC cells.
“leptin inhibits the firing rate of NPY/AgRP neurons (189), while simultaneously depolarizing POMC neurons (42), and also activates PI3K signaling in the latter cells (204).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [42]
POMC neurons are depolarized by leptin, leading to release of α-MSH, which mediates anorexigenic effects through activation of melanocortin receptors.
“POMC neurons are depolarized by leptin, leading to release of α-melanocyte stimulating hormone (α-MSH), a POMC-derived neuropeptide that mediates its anorexigenic effects through activation of melanocortin receptors (Cone, 2005; Cowley et al., 2001; Schwartz et al., 2000).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Cowley et al., 2001
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Cites
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419 · see citing works
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
mouse brain in stereotaxic coordinates
Franklin, K. B. J., & Paxinos, G. (1997) · Cited by 3,258 · see citing works
Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R., & Burn, P. (1995) · Science · doi:10.1126/science.7624778 · Cited by 3,243 · see citing works
Effects of Recombinant Leptin Therapy in a Child with Congenital Leptin Deficiency
Farooqi, I. S., Jebb, S. A., Langmack, G., Lawrence, E., Cheetham, C. H., Prentice, A. M., Hughes, I. A., McCamish, M. A., & O'Rahilly, S. (1999) · New England Journal of Medicine · doi:10.1056/nejm199909163411204 · Cited by 1,998 · see citing works
Interacting Appetite-Regulating Pathways in the Hypothalamic Regulation of Body Weight
Kalra, S. P., Dube, M. G., Pu, S., Xu, B., Horváth, T. L., & Kalra, P. S. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.1.0357 · Cited by 1,556 · see citing works
Physiological response to long-term peripheral and central leptin infusion in lean and obese mice.
Halaas, J. L., Boozer, C., Blair-West, J., Fidahusein, N., Denton, D. A., & Friedman, J. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.16.8878 · Cited by 1,033 · see citing works
Receptor-mediated regional sympathetic nerve activation by leptin.
Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L., & Sivitz, W. I. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119532 · Cited by 979 · 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
Leptin Receptor Immunoreactivity in Chemically Defined Target Neurons of the Hypothalamus
Håkansson, M., Brown, H., Ghilardi, N., Skoda, R. C., & Meister, B. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-01-00559.1998 · Cited by 731 · see citing works
A Unique Metalolic Sysdrone Causes Obesity in the Melanocortin-3 Receptor-Deficient Mouse
Butler, A. A., Kesteson, R. A., Khong, K., Cullen, M. J., Pelleymounter, M. A., DeKoning, J., Baetscher, M., & Cone, R. D. (2000) · Endocrinology · doi:10.1210/endo.141.9.7791 · Cited by 703 · see citing works
Self-citationLeptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels
Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D., & Ashford, M. L. J. (1997) · Nature · doi:10.1038/37379 · Cited by 628 · see citing works
Integration of NPY, AGRP, and Melanocortin Signals in the Hypothalamic Paraventricular Nucleus
Cowley, M. A., Pronchuk, N., Fan, W., Dinulescu, D. M., Colmers, W. F., & Cone, R. D. (1999) · Neuron · doi:10.1016/s0896-6273(00)80829-6 · Cited by 616 · see citing works
Self-citationBagnol, D., Lu, X.-Y., Kaelin, C. B., Day, H. E. W., Ollmann, M., Gantz, I., Akil, H., Barsh, G. S., & Watson, S. J. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-18-j0004.1999 · Cited by 425 · see citing works
Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic
Haynes, W. G., Morgan, D. A., Djalali, A., Sivitz, W. I., & Mark, A. L. (1999) · Hypertension · doi:10.1161/01.hyp.33.1.542 · Cited by 358 · see citing works
The Central Melanocortin System and Energy Homeostasis
Cone, R. D. (1999) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(99)00153-8 · Cited by 351 · see citing works
Self-citationHorváth, T. L., Bechmann, I., Naftolin, F. N., Kalra, S. P., & Léránth, C. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00184-4 · Cited by 301 · see citing works
Broberger, C., Landry, M., Wong, H., Walsh, J. N., & Hökfelt, T. G. M. (2008) · Neuroendocrinology · doi:10.1159/000127265 · Cited by 298 · see citing works
Kim, M. S., Small, C. J., Stanley, S. A., Morgan, D. G. A., Seal, L. J., Kong, W. M., Edwards, C. M. B., Abusnana, S., Sunter, D., Ghatei, M. A., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8857 · Cited by 256 · see citing works
Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus.
Glaum, S. R., Hara, M., Bindokas, V. P., Lee, C. C., Polonsky, K. S., Bell, G. I., & Miller, R. J. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09211-9 · Cited by 173 · see citing works
́ry, A. C., ̈rcs, T. G., & Palkovits, M. (1990) · Brain Research · doi:10.1016/0006-8993(90)91253-d · Cited by 120 · see citing works
Grieco, P., Balse, P., Weinberg, D., MacNeil, T., & Hruby, V. J. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm000211e · Cited by 116 · see citing works
King, P., Widdowson, P. S., Doods, H. N., & Williams, G. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0730641.x · Cited by 98 · see citing works
Lee, K., Dixon, A. K., Richardson, P. J., & Pinnock, R. D. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.439ac.x · Cited by 90 · see citing works
Opioids Hyperpolarize β-Endorphin Neurons via μ-Receptor Activation of a Potassium Conductance
Kelly, M. J., Loose, M. D., & Rønnekleiv, O. K. (2008) · Neuroendocrinology · doi:10.1159/000125597 · Cited by 86 · see citing works
Leptin depolarizes rat hypothalamic paraventricular nucleus neurons
Powis, J. E., Bains, J. S., & Ferguson, A. V. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.274.5.r1468 · Cited by 83 · see citing works
Young, J. I., Otero, V., Cerdán, M. G., Falzone, T. L., Chan, E., Low, M. J., & Rubinstein, M. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-17-06631.1998 · Cited by 80 · see citing works
Self-citationShiraishi, T., Sasaki, K., Niijima, A., & Oomura, Y. (1999) · Nutrition · doi:10.1016/s0899-9007(99)00088-x · Cited by 76 · see citing works
Horváth, T. L., Naftolin, F. N., & Leranth, C. (1992) · Neuroscience · doi:10.1016/0306-4522(92)90323-t · Cited by 58 · see citing works
Slugg, R. M., Hayward, M. D., Rønnekleiv, O. K., Low, M. J., & Kelly, M. J. (2000) · Neuroendocrinology · doi:10.1159/000054589 · Cited by 23 · see citing works
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Flagged first, then by citations
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Sorted by citations
Adipose Tissue as an Endocrine Organ
Kershaw, E. E., & Flier, J. S. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0395 · Cited by 5,522 · see citing works
Central nervous system control of food intake and body weight
Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S., & Schwartz, M. W. (2006) · Nature · doi:10.1038/nature05026 · Cited by 2,503 · see citing works
Gut hormone PYY3-36 physiologically inhibits food intake
Batterham, R. L., Cowley, M. A., Small, C. J., Herzog, H., Cohen, M. A., Dakin, C. L., Wren, A. M., Brynes, A. E., Low, M. J., Ghatei, M. A., et al. (2002) · Nature · doi:10.1038/nature00887 · Cited by 2,351 · see citing works
Self-citationGarvey, W. T., Mechanick, J. I., Brett, E. M., Garber, A. J., Hurley, D. L., Jastreboff, A. M., Nadolsky, K., Pessah-Pollack, R., & Plodkowski, R. (2016) · Endocrine Practice · doi:10.4158/ep161365.gl · Cited by 1,914 · see citing works
Leptin Regulates Bone Formation via the Sympathetic Nervous System
Takeda, S., Elefteriou, F., Levasseur, R., Liu, X., Zhao, L., Parker, K. L., Armstrong, D., Ducy, P., & Karsenty, G. (2002) · Cell · doi:10.1016/s0092-8674(02)01049-8 · Cited by 1,735 · see citing works
Adipose Tissue as an Endocrine Organ
Ahima, R. S., & Flier, J. S. (2000) · Trends in Endocrinology & Metabolism · doi:10.1016/s1043-2760(00)00301-5 · Cited by 1,608 · see citing works
Inhibition of Food Intake in Obese Subjects by Peptide YY <sub>3–36</sub>
Batterham, R. L., Cohen, M. A., Ellis, S. M., Le Roux, C. W., Withers, D. J., Frost, G. S., Ghatei, M. A., & Bloom, S. R. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa030204 · Cited by 1,604 · see citing works
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
Saper, C. B., Chou, T. C., & Elmquist, J. K. (2002) · Neuron · doi:10.1016/s0896-6273(02)00969-8 · Cited by 1,120 · see citing works
Leptin and Obesity: Role and clinical implication.
Obradovic, M., Sudar-Milovanovic, E., Soskic, S., Essack, M., Arya, S., Stewart, A. J., Gojobori, T., & Isenovic, E. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.585887 · Cited by 1,121 · see citing works
Mechanisms of leptin action and leptin resistance.
Myers, M. G., Cowley, M. A., & Münzberg, H. (2008) · Annual Review of Physiology · doi:10.1146/annurev.physiol.70.113006.100707 · Cited by 1,074 · 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
Deconstruction of a neural circuit for hunger
Atasoy, D., Betley, J. N., Su, H. H., & Sternson, S. M. (2012) · Nature · doi:10.1038/nature11270 · Cited by 969 · 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
Self-citationLeptin receptor signaling in POMC neurons is required for normal body weight homeostasis
Balthasar, N., Coppari, R., McMinn, J., Liu, S. M., Lee, C. E., Tang, V., Kenny, C. D., McGovern, R. A., Chua, S. C., Elmquist, J. K., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.004 · Cited by 935 · see citing works
Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding
Hommel, J. D., Trinko, R., Sears, R. M., Georgescu, D., Liu, Z.-W., Gao, X.-B., Thurmon, J. J., Marinelli, M., & DiLeone, R. J. (2006) · Neuron · doi:10.1016/j.neuron.2006.08.023 · Cited by 902 · see citing works
Neuropeptide Transmission in Brain Circuits
van den Pol, A. N. (2012) · Neuron · doi:10.1016/j.neuron.2012.09.014 · Cited by 810 · see citing works
Diabetes, Obesity, and the Brain
Schwartz, M. W., & Porte, D. (2005) · Science · doi:10.1126/science.1104344 · Cited by 841 · see citing works
Dhillon, H., Zigman, J. M., Ye, C., Lee, C. E., McGovern, R. A., Tang, V., Kenny, C. D., Christiansen, L. M., White, R. D., Edelstein, E. A., et al. (2006) · Neuron · doi:10.1016/j.neuron.2005.12.021 · Cited by 791 · see citing works
Self-citationNeurobiology of food intake in health and disease
Morton, G. J., Meek, T. H., & Schwartz, M. W. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3745 · Cited by 748 · see citing works
Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice
Münzberg, H., Flier, J. S., & Bjørbæk, C. (2004) · Endocrinology · doi:10.1210/en.2004-0726 · Cited by 737 · see citing works
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 · see citing works
Self-citationGlucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity
Parton, L. E., Ye, C. P., Coppari, R., Enriori, P. J., Choi, B., Zhang, C.-Y., Xu, C., Vianna, C. R., Balthasar, N., Lee, C. E., et al. (2007) · Nature · doi:10.1038/nature06098 · Cited by 700 · see citing works
Self-citationInsulin Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production
Könner, A. C., Janoschek, R., Plum, L., Jordan, S. D., Rother, E., Ma, X., Xu, C., Enriori, P., Hampel, B., Barsh, G. S., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.004 · Cited by 695 · see citing works
Self-citationLeptin 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
Sensory Detection of Food Rapidly Modulates Arcuate Feeding Circuits
Chen, Y., Lin, Y.-C., Kuo, T.-W., & Knight, Z. A. (2015) · Cell · doi:10.1016/j.cell.2015.01.033 · Cited by 660 · 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-citationThyroid dysfunction and diabetes mellitus: two closely associated disorders
Biondi, B., Kahaly, G. J., & Robertson, R. P. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00163 · Cited by 598 · see citing works
Leptin in Human Physiology and Pathophysiology
Mantzoros, C. S., Magkos, F., Brinkoetter, M., Sienkiewicz, E., Dardeno, T. A., Kim, S.-Y., Hamnvik, O.-P. R., & Koniaris, A. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00315.2011 · Cited by 593 · see citing works
Wadden, T. A., Foreyt, J. P., Foster, G. D., Hill, J. O., Klein, S., O'Neil, P. M., Perri, M. G., Pi‐Sunyer, F. X., Rock, C. L., Erickson, J. S., et al. (2011) · Obesity · doi:10.1038/oby.2010.147 · Cited by 558 · see citing works
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 · see citing works
Self-citationMolecular and anatomical determinants of central leptin resistance
Münzberg, H., & Myers, M. G. (2005) · Nature Neuroscience · doi:10.1038/nn1454 · Cited by 550 · see citing works
The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology
Tao, Y.-X. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0037 · Cited by 531 · see citing works
Metabolism and Circadian Rhythms—Implications for Obesity
Froy, O. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0014 · Cited by 505 · see citing works
Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche
Lee, D. A., Bedont, J. L., Pak, T., Wang, H., Song, J., Miranda-Angulo, A., Takiar, V., Charubhumi, V., Balordi, F., Takebayashi, H., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3079 · Cited by 502 · see citing works
Loss of GABAergic Signaling by AgRP Neurons to the Parabrachial Nucleus Leads to Starvation
Wu, Q., Boyle, M. P., & Palmiter, R. D. (2009) · Cell · doi:10.1016/j.cell.2009.04.022 · Cited by 465 · see citing works
Hypothalamic inflammation in obesity and metabolic disease
Jais, A., & Brüning, J. C. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88878 · Cited by 474 · see citing works
Obesity in mice with adipocyte-specific deletion of clock component Arntl
Paschos, G. K., Ibrahim, S., Song, W.-L., Kunieda, T., Grant, G., Reyes, T. M., Bradfield, C. A., Vaughan, C. H., Eiden, M., Masoodi, M., et al. (2012) · Nature Medicine · doi:10.1038/nm.2979 · Cited by 465 · see citing works
Coppari, R., Ichinose, M., Lee, C. E., Pullen, A. E., Kenny, C. D., McGovern, R. A., Tang, V., Liu, S. M., Ludwig, T., Chua, S. C., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2004.12.004 · Cited by 457 · see citing works
The circadian regulation of food intake
Challet, E. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0210-x · Cited by 428 · see citing works
Varela, L., & Horvath, T. L. (2012) · The EMBO Reports · doi:10.1038/embor.2012.174 · Cited by 426 · see citing works
The Catabolic Action of Insulin in the Brain Is Mediated by Melanocortins
Benoit, S. C., Air, E. L., Coolen, L. M., Strauss, R., Jackman, A., Clegg, D. J., Seeley, R. J., & Woods, S. C. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09048.2002 · Cited by 417 · see citing works
Tong, Q., Ye, C., McCrimmon, R. J., Dhillon, H., Choi, B., Kramer, M. D., Yu, J., Yang, Z., Christiansen, L. M., Lee, C. E., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.04.001 · Cited by 413 · see citing works
Overlapping Brain Circuits for Homeostatic and Hedonic Feeding
Rossi, M. A., & Stuber, G. D. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.021 · Cited by 415 · see citing works
Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour
Fetissov, S. O. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.150 · Cited by 403 · see citing works
Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat
Dodd, G. T., Decherf, S., Loh, K., Simonds, S. E., Wiede, F., Balland, E., Merry, T. L., Münzberg, H., Zhang, Z.-Y., Kahn, B. B., et al. (2015) · Cell · doi:10.1016/j.cell.2014.12.022 · Cited by 398 · see citing works
Self-citationHill, J. W., Elias, C. F., Fukuda, M., Williams, K. W., Berglund, E. D., Holland, W. L., Cho, Y.-R., Chuang, J.-C., Xu, Y., Choi, M., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.002 · Cited by 391 · see citing works
Gao, Q., Wolfgang, M. J., Neschen, S., Morino, K., Horvath, T. L., Shulman, G. I., & Fu, X.-Y. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0303992101 · Cited by 385 · see citing works
Self-citationBrennan, A. M., & Mantzoros, C. S. (2006) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0196 · Cited by 374 · see citing works
Williams, K. W., Margatho, L. O., Lee, C. E., Choi, M., Lee, S., Scott, M. M., Elias, C. F., & Elmquist, J. K. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3118-09.2010 · Cited by 352 · see citing works
Neurobiology of Feeding and Energy Expenditure
Gao, Q., & Horvath, T. L. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094324 · Cited by 346 · see citing works
Leptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
“Moreover, NPY/AgRP neurons inhibit POMC neurons through release of the inhibitory neurotransmitter GABA (42), and recent work suggests that loss of GABAergic signaling by AgRP neurons projecting to the parabrachial nucleus causes profound anorexia (201).”
BackgroundInfluentialThe TRH neuron: a hypothalamic integrator of energy metabolism
Lechan, R. M., & Fekete, C. (2006) · Progress in brain research · doi:10.1016/s0079-6123(06)53012-2 · Cited by 338 · see citing works
Central and Peripheral Regulation of Food Intake and Physical Activity: Pathways and Genes
Lenard, N. R., & Berthoud, H. (2008) · Obesity · doi:10.1038/oby.2008.511 · Cited by 338 · see citing works
Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding
Kim, J. G., Suyama, S., Koch, M., Jin, S., Argente-Arizon, P., Argente, J., Liu, Z.-W., Zimmer, M. R., Jeong, J. K., Szigeti-Buck, K., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3725 · Cited by 336 · see citing works
Self-citationDifferential Sensitivity to Central Leptin and Insulin in Male and Female Rats
Clegg, D. J., Riedy, C. A., Smith, K. A. B., Benoit, S. C., & Woods, S. C. (2003) · Diabetes · doi:10.2337/diabetes.52.3.682 · Cited by 332 · see citing works
Münzberg, H., Huo, L., Nillni, E. A., Hollenberg, A. N., & Bjørbæk, C. (2003) · Endocrinology · doi:10.1210/en.2002-221037 · Cited by 328 · see citing works
Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons
Schaeffer, M., Langlet, F., Lafont, C., Molino, F., Hodson, D. J., Roux, T., Lamarque, L., Verdié, P., Bourrier, E., Dehouck, B., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1212137110 · Cited by 325 · see citing works
Breton, J., Tennoune, N., Lucas, N., Francois, M., Legrand, R., Jacquemot, J., Goichon, A., Guérin, C., Peltier, J., Pestel-Caron, M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.10.017 · Cited by 321 · see citing works
Hypothalamic Survival Circuits: Blueprints for Purposive Behaviors
Sternson, S. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.018 · Cited by 313 · see citing works
Mandelblat-Cerf, Y., Ramesh, R. N., Burgess, C. R., Patella, P., Yang, Z., Lowell, B. B., & Andermann, M. L. (2015) · eLife · doi:10.7554/elife.07122 · Cited by 290 · see citing works
Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons
Wang, D., He, X., Zhao, Z., Feng, Q., Lin, R., Sun, Y., Ding, T., Xu, F., Luo, M., & Zhan, C. (2015) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2015.00040 · Cited by 298 · 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
Self-citationCircadian Clocks and Metabolism
Marcheva, B., Ramsey, K. M., Peek, C. B., Affinati, A., Maury, E., & Bass, J. (2013) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-25950-0_6 · Cited by 282 · see citing works
Enriori, P. J., Evans, A. E., Sinnayah, P., & Cowley, M. A. (2006) · Obesity · doi:10.1038/oby.2006.319 · Cited by 281 · see citing works
Self-citationRole of the gut-brain axis in energy and glucose metabolism
Wachsmuth, H. R., Weninger, S. N., & Duca, F. A. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00677-w · Cited by 269 · see citing works
Shi, Y.-C., Lau, J., Lin, Z., Zhang, H., Zhai, L., Sperk, G., Heilbronn, R., Mietzsch, M., Weger, S., Huang, X.-F., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.01.006 · Cited by 266 · see citing works
Seizures accelerate functional integration of adult-generated granule cells
Overstreet-Wadiche, L. S., Bromberg, D. A., Bensen, A. L., & Westbrook, G. L. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5508-05.2006 · Cited by 266 · see citing works
Recinella, L., Orlando, G., Ferrante, C., Chiavaroli, A., Brunetti, L., & Leone, S. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.578966 · Cited by 261 · see citing works
The adipocyte as an active participant in energy balance and metabolism
Badman, M. K., & Flier, J. S. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.058 · Cited by 256 · see citing works
The Temperature Dependence of Sleep
Harding, E. C., Franks, N. P., & Wisden, W. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00336 · Cited by 261 · see citing works
“POMC oppose the action of AgRP neurons and are activated by leptin (Cowley et al., 2001).”
BackgroundEffects of Chronic Social Stress on Obesity
Scott, K. A., Melhorn, S. J., & Sakai, R. R. (2012) · Current Obesity Reports · doi:10.1007/s13679-011-0006-3 · Cited by 251 · see citing works
Fu, L.-Y., & van den Pol, A. N. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2098-10.2010 · Cited by 243 · see citing works
Kievit, P., Halem, H., Marks, D. L., Dong, J. Z., Glavas, M. M., Sinnayah, P., Pranger, L., Cowley, M. A., Grove, K. L., & Culler, M. D. (2013) · Diabetes · doi:10.2337/db12-0598 · Cited by 231 · 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
Self-citationLeptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons
Huo, L., Gamber, K., Greeley, S., Silva, J., Huntoon, N., Leng, X.-H., & Bjørbæk, C. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.05.003 · Cited by 226 · see citing works
“POMC neurons are depolarized by leptin, leading to release of α-melanocyte stimulating hormone (α-MSH), a POMC-derived neuropeptide that mediates its anorexigenic effects through activation of melanocortin receptors (Cone, 2005; Cowley et al., 2001; Schwartz et al., 2000).”
Integrative neurocircuits that control metabolism and food intake
Brüning, J. C., & Fenselau, H. (2023) · Science · doi:10.1126/science.abl7398 · Cited by 214 · see citing works
PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice
Banno, R., Zimmer, D., De Jonghe, B. C., Atienza, M., Rak, K., Yang, W., & Bence, K. K. (2010) · Journal of Clinical Investigation · doi:10.1172/jci39620 · Cited by 214 · see citing works
Zhang, G., Bai, H., Zhang, H., Dean, C., Wu, Q., Li, J., Guariglia, S., Meng, Q., & Cai, D. (2011) · Neuron · doi:10.1016/j.neuron.2010.12.036 · Cited by 208 · see citing works
Hunger neurons drive feeding through a sustained, positive reinforcement signal.
Chen, Y., Lin, Y.-C., Zimmerman, C. A., Essner, R. A., & Knight, Z. A. (2016) · eLife · doi:10.7554/elife.18640 · Cited by 196 · 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
Neurotrophic factor control of satiety and body weight
Xu, B., & Xie, X. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.24 · Cited by 203 · see citing works
Immunotherapy for cardiovascular disease
Lutgens, E., Atzler, D., Döring, Y., Duchene, J., Steffens, S., & Weber, C. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz283 · Cited by 192 · see citing works
Roa, J., & Herbison, A. E. (2012) · Endocrinology · doi:10.1210/en.2012-1470 · Cited by 192 · see citing works
The Sense of Smell Impacts Metabolic Health and Obesity
Riera, C. E., Tsaousidou, E., Halloran, J., Follett, P., Hahn, O., Pereira, M. M. A., Ruud, L. E., Alber, J., Tharp, K., Anderson, C. M., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.015 · Cited by 191 · see citing works
PI3K integrates the action of insulin and leptin on hypothalamic neurons
Xu, A. W. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200524301 · Cited by 420 · see citing works
Ernst, M. B., Wunderlich, C. M., Hess, S., Paehler, M., Mesaros, A., Koralov, S. B., Kleinridders, A., Husch, A., Münzberg, H., Hampel, B., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5712-08.2009 · Cited by 185 · see citing works
Comparison of Combined Bupropion and Naltrexone Therapy for Obesity with Monotherapy and Placebo
Greenway, F. L., Dunayevich, E., Tollefson, G., Erickson, J., Guttadauria, M., Fujioka, K., Cowley, M. A., & for the NB-201 Study Group (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1350 · Cited by 179 · see citing works
Self-citationBrain regulation of energy balance and body weight
Rui, L. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9261-9 · Cited by 168 · see citing works
Selective leptin resistance revisited
Mark, A. L. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00180.2013 · Cited by 162 · see citing works
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 · see citing works
GABA depolarization is required for experience-dependent synapse unsilencing in adult-born neurons
Chancey, J. H., Adlaf, E. W., Sapp, M. C., Pugh, P. C., Wadiche, J. I., & Overstreet-Wadiche, L. S. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.0781-13.2013 · Cited by 152 · see citing works
Serotonin and the regulation of mammalian energy balance
Donovan, M. H., & Tecott, L. H. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00036 · Cited by 150 · 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
Zheng, H., Corkern, M., Stoyanova, I., Patterson, L. M., Tian, R., & Berthoud, H.-R. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00781.2002 · Cited by 135 · see citing works
Melanocortin-4 Receptor Mediates Chronic Cardiovascular and Metabolic Actions of Leptin
Tallam, L. S., da Silva, A. A., & Hall, J. E. (2006) · Hypertension · doi:10.1161/01.hyp.0000227966.36744.d9 · Cited by 133 · see citing works
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 · see citing works
- Authors
- Cowley, M. A., Smart, J. L., Rubinstein, M., Cerdán, M. G., Diano, S., Horvath, T. L., Cone, R. D., & Low, M. J.
- Affiliations
- Oregon Health & Science University (US)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Corresponding author
- Cone, Roger D.
- Venue
- Nature
- Published
- 2001-05
- Volume
- 411
- Issue
- 6836
- Pages
- 480-484
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1506453366
- Cited by
- 2,356
- References
- 30
- Citations by year
- 2026: 44 · 2025: 67 · 2024: 96 · 2023: 90 · 2022: 79 · 2021: 82 · 2020: 105 · 2019: 84 · 2018: 121 · 2017: 104 · 2016: 123 · 2015: 117 · 2014: 93 · 2013: 107 · 2012: 125
- FWCI
- 30.52
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Digital Commons - George Fox University (George Fox University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- 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
- leptin, proopiomelanocortin neurons, arcuate nucleus, hypothalamus, leptin resistance, neuropeptide Y neurons, GABAergic inhibition, neuronal networks, food intake regulation, obesity, hyperphagia, energy balance
- MeSH terms
- Action Potentials, Animals, Anorexia, Arcuate Nucleus of Hypothalamus, Electrophysiology, Evoked Potentials, gamma-Aminobutyric Acid, Luminescent Proteins, Male, Mice, Inbred C57BL, Nerve Net, Neural Inhibition, Neurons, Neuropeptide Y, Pro-Opiomelanocortin, Leptin, Animals, Genetically Modified, Green Fluorescent Proteins, Mice
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