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Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite
Open accessAbstract
The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.
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“neurons in the VTA and/or NAc express GLP-1 (24,25), ghrelin (26,27), leptin (28,29), insulin (30), orexin (31) and melanocortin receptors (32).”
From Obesity and addiction: Neurobiological overlaps (2013) · cites this paper as [26]
In the citing paper
“Moreover, neurons in VTA and/or nucleus accumbens (NAc) express glucagon-like peptide-1 (11,12), ghrelin (13,14), leptin (15,16), insulin (17), orexin (18), and melanocortin receptors (19).”
From The Addictive Dimensionality of Obesity (2013) · cites this paper as [13]
In the citing paper
“In contrast, ghrelin action directly within the VTA appears to activate dopamine neurons, increase accumbens dopamine turnover, and increase food intake”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [1]
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Elevated activity of the mesolimbic dopamine system promotes feeding during pregnancy in mice
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“In addition to promoting the consumption of palatable foods, VTA dopamine activity is also involved in promoting food seeking behaviors and reinforcement associated with food consumption in energy deprived mice [9,14,15,20].”
Diene, G., Benvegnu, G., Brochado, C., Clerc, A., Jouret, B., Montastier, É., Grunenwald, S., Poitou, C., Héron, D., Portes, V. D., et al. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag081 · Cited by 2
Ghrelin in the Regulation of GH Secretion and Other Pituitary Hormones
Lanfranco, F., Baldi, M., Motta, G., Minetto, M. A., Marotta, F., Gasco, V., & Ghigo, E. (2011) · Humana Press eBooks · doi:10.1007/978-1-60761-317-6_2 · Cited by 2
“Additional data have shown that ghrelin can activate the mesoaccumbal dopamine system in the ventral tegmental area of mice and rats [83–85] and protect nigral dopaminergic neurons by reducing apoptosis [86].”
BackgroundThe Role of the Ghrelin Receptor in Appetite and Energy Metabolism
Stark, R., & Andrews, Z. B. (2014) · The Receptors · doi:10.1007/978-1-4939-0823-3_3 · Cited by 2
“Moreover, ghrelin increases food intake by modulating the reward-related motivation in the midbrain dopamine system (Abizaid 2009; Abizaid et al. 2006; Naleid et al. 2005).”
BackgroundSelf-citationThe Ghrelin Receptor: A Novel Therapeutic Target for Obesity
Schellekens, H., Dinan, T. G., & Cryan, J. F. (2014) · The Receptors · doi:10.1007/978-1-4939-0823-3_6 · Cited by 2
“Moreover, peripheral and central ghrelin administration has been shown to directly enhance ghrelin-mediated activation of dopaminergic neurons within the VTA (Abizaid et al. 2006).”
BackgroundCrosstalk between maternal perinatal obesity and offspring dopaminergic circuitry
Yasumoto, Y., & Horváth, T. L. (2020) · Journal of Clinical Investigation · doi:10.1172/jci138123 · Cited by 2
“In particular, dopamine (DA) within the mesocorticolimbic DA (MCL-DA) system regulates feeding as well (5).”
BackgroundThe GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning
Marion, C., Zizzari, P., Denis, R., Hassouna, R., Chebani, Y., Lesté-Lasserre, T., Doat, H., Pen, G. L., Cota, D., Noble, F., et al. (2021) · Journal of Endocrinology · doi:10.1530/joe-20-0576 · Cited by 2
“…(Kojima et al. 1999), enhanced fat storage and enhanced food intake, mediated by its action on brain energy homeostasis centers (Nakazato, et al. 2001; Theander-Carrillo, et al. 2006; Tschop, et al. 2000) and hedonic circuits (Abizaid, et al. 2006; Jerlhag, et al. 2007; Naleid, et al. 2005).”
Morari, J., Haddad-Tóvolli, R., Nogueira, P. A. S., Teixeira, C. J., Maróstica, R., Tobar, N., Ramos, C. D., Velloso, L. A., Bóbbo, V. C. D., & Anhê, G. F. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111646 · Cited by 2
Özkan-Kotiloğlu, S., Kaya-Akyüzlü, D., Güven, E., Doğan, Ö., ERTAN, E. A., & İlhan, İ. Ö. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09585-4 · Cited by 2
“Moreover, it has been shown that ghrelin regulates dopaminergic neuron signaling and may be involved in development and maintenance of addictive disease and also reward related craving [10, 11].”
Reikhardt, B. A., & Shabanov, P. D. (2022) · Reviews on Clinical Pharmacology and Drug Therapy · doi:10.17816/rcf203229-254 · Cited by 2
“Это предполагает, что грелин модулирует синаптические механизмы, повышающие чувствительность DA-нейронов к активирующим факторам [170].”
Nogueiras, R., & Seeley, R. J. (2012) · Molecular Metabolism · doi:10.1016/j.molmet.2012.08.002 · Cited by 2
“For example, the dopaminergic system plays an important role as a mediator of the actions of ghrelin on food intake [4], spatial memories [8], and locomotor activity [9].”
BackgroundTransdisciplinary Tobacco Use Research Centers: Research achievements and future implications
Baker, T. B., Cummings, K. M., Hatsukami, D. K., Johnson, C. A., Lerman, C. E., NIAURA, R. S., & O’Malley, S. S. (2009) · Nicotine & Tobacco Research · doi:10.1093/ntr/ntp112 · Cited by 2
Hege, M. A., Stingl, K. T., & Preissl, H. T. (2014) · Springer eBooks · doi:10.1007/978-3-642-33045-2_43 · Cited by 2
Facteurs de la faim et de la satiété dans la régulation du plaisir alimentaire
Fetissov, S. O. (2016) · Biologie Aujourd hui · doi:10.1051/jbio/2016025 · Cited by 4
Ghrelin: Neuropeptide Regulator of Metabolism
Enriori, P. J., Andrews, Z. B., & Cowley, M. A. (2012) · Humana Press eBooks · doi:10.1007/978-1-61779-903-7_6 · Cited by 2
“Due to the fact that ghrelin activates the mesolimbic dopamine pathway [ 70, 71 ] , it is possible that the GHSR regulates food intake, body weight, and adiposity by enhancing the reward value of food, particularly high-fat food [ 72 ] .”
BackgroundSelf-citationSun exposure stimulates appetite in males
Diéguez, C., & Nogueiras, R. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00592-y · Cited by 2
Koob, G. F., Arends, M. A., McCracken, M. L., & Moal, M. L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-816988-9.00001-1 · Cited by 2
Genetic and Developmental Origins of Food Preferences and Obesity Risk: The Role of Dopamine
Silveira, P. P., Kennedy, J. L., Sokolowski, M. B., Levitan, R. D., & Meaney, M. J. (2014) · Research and perspectives in endocrine interactions · doi:10.1007/978-3-319-02591-9_11 · Cited by 2
Żurawicki, L. (2010) · Springer eBooks · doi:10.1007/978-3-540-77829-5_2 · Cited by 3
Food-Anticipatory Activity: Rat Models and Underlying Mechanisms
Adan, R. A. H. (2020) · Neuromethods · doi:10.1007/978-1-0716-0924-8_18 · Cited by 2
Skibicka, K. P., & Kanoski, S. E. (2016) · doi:10.1002/9781118839317.ch5 · Cited by 2
Peri-adolescent THC exposure does not lead to anxiety-like behavior in adult micePreprint
Šestan-Peša, M., Shanabrough, M., Horváth, T. L., & Miletta, M. C. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.31.274274 · Cited by 2
“GHSR mice were 109 previously generated in our lab [30].”
BackgroundSelf-citationBlundell, J. E., Finlayson, G., & Halford, J. C. G. (2009) · Clinical Obesity in Adults and Children · doi:10.1002/9781444307627.ch11 · Cited by 1
Hormones and the Regulation of Neuronal Voltage-Sensing Ion Channels
Lyons, D. J. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813814-4.00011-0 · Cited by 1
Blum, K., Downs, B. W., Bagchi, D., Wang, G., Thanos, P. K., Elman, I., Jalali, R., Bowirrat, A., Baron, D. A., Soni, D., et al. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-822238-6.00001-7 · Cited by 1
Alternating mealtimes during pregnancy and weaning triggers behavioral changes in adult offspring
Kim, M., Park, J., Han, D., Noh, J.-Y., Ji, E., Lee, S., Kim, C., & Cho, S. (2022) · Reproduction · doi:10.1530/rep-22-0164 · Cited by 1
du Montcel, C. T., & Tolle, V. (2023) · Cahiers de Nutrition et de Diététique · doi:10.1016/j.cnd.2022.12.002 · Cited by 1
Multiple metabolic signals in the CeA regulate feeding: The role of AMPK
Castro, G., Mendes, N. F., Weissmann, L., Quaresma, P. G. F., Saad, M. J. A., & Prada, P. O. (2024) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2024.112232 · Cited by 1
Oxytocin as a modulator of adaptive behavior: integrating ingestive and social mechanisms
Moseley, P. E., Hammock, E. A. D., & Williams, D. L. (2025) · Physiology & Behavior · doi:10.1016/j.physbeh.2025.114992 · Cited by 2
Metadata
- Authors
- 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., Gao, X.-B., & Horvath, T. L.
- Affiliations
- Yale University (US)
- Regeneron (United States) (US)
- University of Cincinnati (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2006-12-01
- Volume
- 116
- Issue
- 12
- Pages
- 3229-3239
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2086950122
- Cited by
- 984
- References
- 58
- Citations by year
- 2026: 23 · 2025: 33 · 2024: 31 · 2023: 34 · 2022: 46 · 2021: 53 · 2020: 44 · 2019: 40 · 2018: 56 · 2017: 66 · 2016: 51 · 2015: 57 · 2014: 60 · 2013: 73 · 2012: 78
- FWCI
- 15.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- Ipsen
- National Institutes of Health (5r01mh057483-13, DK056863)
- Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, Yale University
- National Institute on Alcohol Abuse and Alcoholism (P50AA015632)
- National Institute on Aging (R01AG022880, AG-022880)
- National Institute of Mental Health (R01-MH057483, R01MH014092, MH014092, MH057483, R37MH014092)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK070723, DK-056863, DK-069987, DK 060711, DK 070723, P01DK056863, DK074386, R01DK069987, R01DK074386, R01DK060711)
- National Institute of Neurological Disorders and Stroke (R01NS041725, NS-041725)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- ghrelin, ventral tegmental area, dopaminergic neurons, nucleus accumbens, synaptic plasticity, feeding behavior, appetite, mesolimbic reward circuitry, energy metabolism
- MeSH terms
- Action Potentials, Animals, Appetite, Dopamine, Fluorescent Antibody Technique, Male, Mesencephalon, Mice, Inbred C57BL, Neurons, Nucleus Accumbens, Time Factors, Rats, Sprague-Dawley, Ventral Tegmental Area, Mice, Knockout, Patch-Clamp Techniques, Peptide Hormones, Receptors, G-Protein-Coupled, Mice, Rats, Ghrelin, Receptors, Ghrelin
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