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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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Cites
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AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors
Dietrich, M. O., Bober, J., Ferreira, J. G., Tellez, L. A., Mineur, Y. S., Souza, D. O., Gao, X.-B., Picciotto, M. R., Araújo, I., Liu, Z.-W., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3147 · Cited by 158
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“In addition to its actions on hypothalamic neurons, ghrelin also regulates mesolimbic dopaminergic neurons in the midbrain to modulate more complex aspects of feeding such as food-reward behavior (3, 85, 354, 400, 478).”
BackgroundCentral mechanisms involved in the orexigenic actions of ghrelin
Andrews, Z. B. (2011) · Peptides · doi:10.1016/j.peptides.2011.05.014 · Cited by 160
Self-citationFuel utilization by hypothalamic neurons: roles for ROS
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Self-citationNeuronal control of energy homeostasis
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“port of a role for the mesolimbic reward circuitry in feeding regulation, it was recently found that interfering with ghrelin signaling specifically in the VTA diminished ghrelin-induced feeding [140].”
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Eating beyond metabolic need: how environmental cues influence feeding behavior
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The Role of Ghrelin in Reward-Based Eating
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“Of elevance, GHSRs are highly expressed in the VTA, including dopainergic VTA neurons (12,52).”
BackgroundInfluentialObesity Impairs the Action of the Neuroendocrine Ghrelin System
Zigman, J. M., Bouret, S. G., & Andrews, Z. B. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.09.010 · Cited by 157
“Ghrelin also acts on several other brain regions, including the midbrain dopaminergic system through which it also increases food intake [39] and engages reward-related behaviors associated with a highfat diet (HFD) [40,41].”
BackgroundSelf-citationThe Opioid System and Food Intake: Homeostatic and Hedonic Mechanisms
Nogueiras, R., Romero, A., Vazquez, M. J., Novelle, M. G., López, M., & Diéguez, C. (2012) · Obesity Facts · doi:10.1159/000338163 · Cited by 152
Therapeutic Potential of Targeting the Ghrelin Pathway
Colldén, G., Tschöp, M. H., & Müller, T. D. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18040798 · Cited by 161
Self-citationBDNF and the central control of feeding: accidental bystander or essential player?
Rios, M. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.12.009 · Cited by 159
Shin, A. C., Zheng, H., & Berthoud, H. (2009) · Physiology & Behavior · doi:10.1016/j.physbeh.2009.02.010 · Cited by 153
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Monteleone, A. M., Castellini, G., Volpe, U., Ricca, V., Lelli, L., Monteleone, P., & Maj, M. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.02.020 · Cited by 162
Cottone, P., Sabino, V., Steardo, L., & Zorrilla, E. P. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301430 · Cited by 148
“For example, levels of leptin and ghrelin, appetite-regulatory homeostatic hormones that directly modulate reward neurocircuitry (Hommel et al, 2006; Abizaid et al, 2006; Hao et al, 2006; Shizgal et al, 2001) differed as a result of diet history and perhaps changed before onset of body weight…”
BackgroundMicrobiota‐gut‐brain axis as a regulator of reward processes
García‐Cabrerizo, R., Carbia, C., O’Riordan, K. J., Schellekens, H., & Cryan, J. F. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15284 · Cited by 150
Goldstone, A. P., Prechtl, C. G., Scholtz, S., Miras, A. D., Chhina, N., Durighel, G., Deliran, S. S., Beckmann, C. F., Ghatei, M. A., Ashby, D. R., et al. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.075291 · Cited by 147
Cordeira, J., Frank, L., Sena‐Esteves, M., Pothos, E. N., & Rios, M. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5768-09.2010 · Cited by 147
“Appetite-regulating factors, including leptin, ghrelin, and melanin-concentrating hormone regulate mesolimbic dopaminergic activity and some of their effects on feeding involve this system (Georgescu et al., 2005; Abizaid et al., 2006; Fulton et al., 2006; Hommel et al., 2006).”
BackgroundVucetic, Z., & Reyes, T. M. (2010) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.77 · Cited by 145
Jerlhag, E., & Engel, J. A. (2011) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2011.01.010 · Cited by 135
“In the VTA, GHS-R1A is expressed pre-synaptically as well as on dopaminergic neurons (Abizaid et al., 2006).”
BackgroundSkibicka, K. P., Shirazi, R. H., Rabasa, C., Álvarez-Crespo, M., Neuber, C., Vogel, H., & Dickson, S. L. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.06.004 · Cited by 142
Ghrelin and Dopamine: New Insights on the Peripheral Regulation of Appetite
Abizaid, A. B. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2009.01896.x · Cited by 138
Self-citationGhrelin's Roles in Stress, Mood, and Anxiety Regulation
Chuang, J.-C., & Zigman, J. M. (2010) · International Journal of Peptides · doi:10.1155/2010/460549 · Cited by 144
“-injected ghrelin [38, 41].”
Mani, B. K., & Zigman, J. M. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.10.001 · Cited by 140
“While fasting-induced rebound food intake was unaltered in ghrl / and ghsr / mice [47,49,56,57], pharmacological antagonism of GHSR blunted fasting-induced rebound food intake [56] as did chemogenetic inhibition of mediobasal hypothalamic GHSR-expressing neurons [20].”
BackgroundCan’t or Won’t? Immunometabolic Constraints on Dopaminergic Drive
Treadway, M. T., Cooper, J. A., & Miller, A. H. (2019) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2019.03.003 · Cited by 141
Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back
Coccurello, R., & Maccarrone, M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00271 · Cited by 143
“…heteromers also in the LH-VTA-NAc circuit might help to explain the reduced or even abolished craving for palatable food and drug of abuse, as well as inhibition of NAc DA release induced by systemic or intraVTA pharmacological blockade of GHSR1a (Abizaid et al., 2006; Jerlhag et al., 2010, 2011).”
BackgroundInfluentialEngel, J. A., & Jerlhag, E. (2014) · CNS Drugs · doi:10.1007/s40263-014-0178-y · Cited by 136
“While previous studies pinpointed hypothalamic GHSR1A to be important for ghrelin mediated food intake [12], the findings that ghrelin increases alcohol intake via local injections into either the VTA or LDTg [55], suggest that the cholinergic–dopaminergic reward link is important for ghrelin signaling to regulate alc…”
BackgroundInfluentialSugar Addiction: From Evolution to Revolution
Wiss, D. A., Avena, N. M., & Rada, P. V. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00545 · Cited by 147
“Stomach-derived ghrelin has known action on orexigenic neurons in the hypothalamus, and receptors have been identified in the VTA, hippocampus, and amygdala (97, 98).”
BackgroundNeural Systems Controlling the Drive to Eat: Mind Versus Metabolism
Zheng, H., & Berthoud, H.-R. (2008) · Physiology · doi:10.1152/physiol.00047.2007 · Cited by 131
“In contrast to leptin, the gut hormone ghrelin appears to facilitate foraging behavior and increase reward processing as part of its orexigenic action (1, 27, 39, 72).”
BackgroundSpencer, S. J., Emmerzaal, T. L., Kozicz, T., & Andrews, Z. B. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.10.021 · Cited by 129
Stengel, A., Goebel, M., Wang, L., & Taché, Y. (2009) · Peptides · doi:10.1016/j.peptides.2009.11.019 · Cited by 131
“A single intra-tegmental infusion of ghrelin significantly increases food intake [2].”
Disse, E., Bussier, A.-L., Veyrat‐Durebex, C., Deblon, N., Pfluger, P. T., Tschöp, M. H., Laville, M., & Rohner‐Jeanrenaud, F. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.05.017 · Cited by 136
“In addition, local ghrelin receptor blockade in the VTA blunts rebound feeding following fast [10].”
Self-citationQuarta, D., Francesco, C. D., Melotto, S., Mangiarini, L., Heidbreder, C. A., & Hédou, G. (2008) · Neurochemistry International · doi:10.1016/j.neuint.2008.12.006 · Cited by 127
“Indeed, at the functional level bursting activity of VTA neurons is triggered by central ghrelin stimulation that also increases striatal DA turnover (Abizaid et al., 2006; Jerlhagetal., 2007) and release in theNAc (Jerlhagetal.”
BackgroundCurrent Understanding of the Hypothalamic Ghrelin Pathways Inducing Appetite and Adiposity
Al Massadi, O., López, M., Tschöp, M., Diéguez, C., & Nogueiras, R. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2016.12.003 · Cited by 124
“The interaction between the dopamine system and ghrelin to modulate reward and motivation (extensively reviewed in [80]), and the ability of ghrelin to modulate activity and synaptic input of midbrain dopamine neurons, leads to promotion of appetite [81].”
Self-citationPatterson, Z. R., Khazall, R., MacKay, H., Anisman, H., & Abizaid, A. B. (2013) · Endocrinology · doi:10.1210/en.2012-1834 · Cited by 130
Self-citationFunctional implications of glutamatergic projections to the ventral tegmental area
Geisler, S., & Wise, R. A. (2008) · Reviews in the Neurosciences · doi:10.1515/revneuro.2008.19.4-5.227 · Cited by 125
“Neurotensin afferents of the ventral tegmental area in the rat: [1] re-examination of their origins and [2] responses to acute psychostimulant and antipsychotic drug administration.”
Naef, L., Moquin, L., Bo, G. D., Bruno Giros, A., Gratton, A. P., & Walker, C. D. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.12.037 · Cited by 126
Fasting levels of ghrelin covary with the brain response to food pictures
Kroemer, N. B., Krebs, L., Kobiella, A., Grimm, O., Pilhatsch, M., Bidlingmaier, M., Zimmermann, U. S., & Smolka, M. N. (2012) · Addiction Biology · doi:10.1111/j.1369-1600.2012.00489.x · Cited by 122
“(2008) and (2) anatomical masks of regions with a well-known connection to reward processing (ventral striatum) and numerous ghrelin receptors (hypothalamus and midbrain; Abizaid et al. 2006), whereas spheres of 5-mm radii surrounded the Figure 1 Mean plasma levels of ghrelin.”
BackgroundResultInfluentialFarokhnia, M., Grodin, E. N., Lee, M. R., Oot, E. N., Blackburn, A. N., Stangl, B. L., Schwandt, M. L., Farinelli, L. A., Momenan, R., Ramchandani, V. A., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.226 · Cited by 127
Feeding signals and brain circuitry
Dietrich, M. O., & Horváth, T. L. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.06963.x · Cited by 130
“Direct VTA administration of ghrelin was sufficient to induce food intake, while the blockage of ghrelin’s action in the VTA by infusion of a ghrelin antagonist blocked the orexigenic effect of circulating ghrelin (Abizaid et al., 2006).”
BackgroundMotivation to obtain preferred foods is enhanced by ghrelin in the ventral tegmental area
King, S. J., Isaacs, A. M., O’Farrell, E., & Abizaid, A. B. (2011) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.08.006 · Cited by 128
“Conversely, blocking VTA ghrelin receptors using a selective GHSR antagonist blunts food intake induced by peripheral ghrelin and rebound feeding in mice fasted overnight (Abizaid et al., 2006).”
InfluentialSelf-citationPhysiological Effect of Ghrelin on Body Systems
Akalu, Y., Molla, M. D., Dessie, G., & Ayelign, B. (2020) · International Journal of Endocrinology · doi:10.1155/2020/1385138 · Cited by 129
“-is stimulation increases the frequency and probability of DA release from their projections in the NAcc, PFC, HIP, and amygdala to encourage mesolimbic reward feeding [66, 77] (Figure 6).”
BackgroundStress induced obesity: lessons from rodent models of stress
Patterson, Z. R., & Abizaid, A. B. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00130 · Cited by 128
“Acutely, ghrelin has the unique ability to promote food intake (Nakazato et al., 2001; Currie et al., 2005; Date et al., 2006) an effect that is mediated by the stimulation of distinct hypothalamic, brain stem, and midbrain nuclei (Cowley et al., 2003; Seoane et al., 2003; Abizaid et al., 2006).”
BackgroundSelf-citationObesity – A neuropsychological disease? Systematic review and neuropsychological model
Jauch‐Chara, K., & Oltmanns, K. M. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.12.001 · Cited by 136
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
Identification of SLC38A7 (SNAT7) Protein as a Glutamine Transporter Expressed in Neurons
Hägglund, M. G. A., Sreedharan, S., Nilsson, V. C., Shaik, J. H. A., Almkvist, I., Bäcklin, S., Wränge, Ö., & Fredriksson, R. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.162404 · Cited by 128
Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators
Sánchez-Lasheras, C., Könner, A. C., & Brüning, J. C. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.08.002 · Cited by 127
“Projections from the VTA to the NAc are well characterized regarding their role in drug addiction and the rewarding aspects of food and sex [90,197].”
BackgroundInfluentialHryhorczuk, C., Florea, M., Rodaros, D., Poirier, I., Daneault, C., Des Rosiers, C., Arvanitogiannis, A., Alquier, T., & Fulton, S. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.207 · Cited by 119
“…established that peripherally derived hormones such as leptin and insulin, the levels of which are largely regulated by caloric load and diet composition, target the VTA to affect reward-relevant behaviors and psychostimulant action (Abizaid et al, 2006; Fulton et al, 2006; Labouebe et al, 2013).”
BackgroundInteractions between endocrine and circadian systems
Tsang, A. H. K., Barclay, J. L., & Oster, H. (2013) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0118 · Cited by 130
“Ghrelin stimulates appetite via its actions on the hypothalamic orexigenic peptides, neuropeptide Y and orexin, and on mesolimbic reward centres (Abizaid et al. 2006, Toshinai et al. 2006).”
BackgroundHypothalamic obesity in children
Bereket, A., Kiess, W., Lustig, R. H., Muller, H. L., Goldstone, A. P., Weiss, R., Yavuz, Y., & Hochberg, Z. (2012) · Obesity Reviews · doi:10.1111/j.1467-789x.2012.01004.x · Cited by 117
“Indeed, recent studies have confirmed the specific role of neurotransmitters, including gamma-aminobutyric acid (GABA) (20), dopamine (21), serotonin (22) and histamine (23,24), in hypothalamic weight control.”
BackgroundLandgren, S., Simms, J. A., Hyytiä, P., Engel, J. A., Bartlett, S. E., & Jerlhag, E. (2011) · Addiction Biology · doi:10.1111/j.1369-1600.2010.00280.x · Cited by 117
“In the VTA, GHS-R1A is expressed on dopaminergic neurons (Abizaid et al. 2006) and it has been suggested that GHS-R1A regulates the activity of tegmental dopamine neurons via heterodimerization of the GHSR1A with the dopamine D1-like receptor as well as by the constitutive activity of the GHS-R1A…”
BackgroundThoughts for Food: Brain Mechanisms and Peripheral Energy Balance
Abizaid, A. B., Gao, Q., & Horváth, T. L. (2006) · Neuron · doi:10.1016/j.neuron.2006.08.025 · Cited by 122
Self-citationMacKay, H., Patterson, Z. R., Khazall, R., Patel, S., Tsirlin, D., & Abizaid, A. B. (2013) · Endocrinology · doi:10.1210/en.2012-2044 · Cited by 116
“Tissue sections were processed for either vGlut1 and POMC, or GAD67 and POMC immunofluorescence in a manner similar to previously published (29).”
ResultSelf-citationEating for pleasure or calories
Zheng, H., & Berthoud, H. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.10.011 · Cited by 121
Regulation of fat intake in the absence of flavour signalling
Ferreira, J. G. P., Téllez, L. A., Ren, X., Yeckel, C. W., & de Araújo, I. E. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2011.218289 · Cited by 116
“Our results are also consistent with recent reports that the stomach orexigenic peptide ghrelin, whose secretion is inhibited by nutrient ingestion, acts centrally to induce dopamine release in accumbens (Abizaid et al. 2006; Jerlhag et al. 2010).”
ResultCentral Nervous System Regulation of Energy Metabolism: Ghrelin versus Leptin
Nogueiras, R., Tschöp, M. H., & Zigman, J. M. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1433.054 · Cited by 115
Self-citationGhrelin and food reward: The story of potential underlying substrates
Skibicka, K. P., & Dickson, S. L. (2011) · Peptides · doi:10.1016/j.peptides.2011.05.016 · Cited by 122
“eceptors seems to be required for the excitatory role of ghrelin on TA dopaminergic neurons [2].”
BackgroundInfluentialFletcher, P. J., Rizos, Z., Sinyard, J., Tampakeras, M., & Higgins, G. A. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301509 · Cited by 114
“Recently, they have been shown also to have a modulatory effect on VTA cell firing, and to influence central reward pathways (Abizaid et al, 2006; Fulton et al, 2006; Hommel et al, 2006).”
BackgroundConcomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats
Jerlhag, E., Janson, A. C., Waters, N., & Engel, J. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049557 · Cited by 114
“In the VTA, several mechanisms appear to mediate this effect as nicotinic acetylcholine as well as glutamate receptor antagonists, administered in the VTA, block the ability of ghrelin to active the reward systems, as measured by increased accumbal dopamine, locomotor stimulation and conditioned place preference, and…”
BackgroundThe hypocretins as sensors for metabolism and arousal
Adamantidis, A., & De Lecea, L. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2008.164400 · Cited by 112
“We found that optical stimulation of ChR2-expressing Hcrt neurons increases the probability of NREM and REM sleep-to-wake transitions in vivo (Adamantidis et al. 2007).”
BackgroundMethodInfluentialEnergy regulatory signals and food reward
Figlewicz, D. P., & Sipols, A. J. (2010) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.03.002 · Cited by 116
“…studies demonstrate that ghrelin—which is increased in association with food deprivation—can increase NAc dopamine levels (Jerlhag et al., 2006) and, acting at the VTA, can stimulate feeding (Abizaid et al., 2006; Naleid et al., 2005) and increase dopamine neuronal activity (Abizaid et al., 2006).”
BackgroundWiedmer, P., Nogueiras, R., Broglio, F., D'Alessio, D., & Tschöp, M. H. (2007) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0625 · Cited by 111
“In the ventral tegmental area, ghrelin activates dopaminergic neurons, suggesting that ghrelin might have a role in the rewarding qualities and addictive properties of food”
BackgroundSelf-citationSleep and metabolism: shared circuits, new connections
Adamantidis, A., & de Lecea, L. (2008) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2008.08.007 · Cited by 112
A functional neuroimaging review of obesity, appetitive hormones and ingestive behavior
Burger, K. S., & Berner, L. A. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.04.025 · Cited by 110
“More comprehensive reviews detail the mechanisms through which endocrine functioning influences hunger and satiety to maintain homeostasis and have documented alterations in hormone levels in obese individuals [31-33].”
BackgroundThe Mysterious Food-Entrainable Oscillator: Insights from Mutant and Engineered Mouse Models
Pendergast, J. S., & Yamazaki, S. (2018) · Journal of Biological Rhythms · doi:10.1177/0748730418789043 · Cited by 111
Neural circuits and motivational processes for hunger
Sternson, S. M., Nicholas Betley, J., & Cao, Z. F. H. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.04.006 · Cited by 108
Signaling through the ghrelin receptor modulates hippocampal function and meal anticipation in mice
Davis, J. F., Choi, D. L., Clegg, D., & Benoit, S. (2010) · Physiology and Behavior · doi:10.1016/j.physbeh.2010.10.017 · Cited by 110
Cabral, A., Valdivia, S., Fernández, G., Reynaldo, M., & Perelló, M. (2014) · Journal of Neuroendocrinology · doi:10.1111/jne.12168 · Cited by 114
The neurobiology of appetite: hunger as addiction.
Dagher, A. (2009) · International Journal of Obesity · doi:10.1038/ijo.2009.69 · Cited by 108
Galić, S., Loh, K., Murray‐Segal, L., Steinberg, G. R., Andrews, Z. B., & Kemp, B. E. (2018) · eLife · doi:10.7554/elife.32656 · Cited by 112
“For example, both ghrelin- and ghrelin receptor knockout mice show attenuated feeding in response to repeated overnight fasts (Abizaid et al., 2006).”
BackgroundSelf-citationGahete, M. D., Córdoba‐Chacón, J., Kineman, R. D., Luque, R. M., & Castano, J. P. (2011) · Peptides · doi:10.1016/j.peptides.2011.09.019 · Cited by 109
“In this study, they showed that in mice and rats, ghrelin bound to neurons of the ventral tegmental area (VTA) and, in a GHSRdependent manner, increased dopamine neuronal activity, synapse formation and dopamine turnover in the nucleus accumbens [1].”
BackgroundArgument for a non‐linear relationship between severity of human obesity and dopaminergic tone
Horstmann, A., Fenske, W. K., & Hankir, M. K. (2015) · Obesity Reviews · doi:10.1111/obr.12303 · Cited by 109
Ghrelin in psychiatric disorders – A review
Wittekind, D. A., & Kluge, M. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.11.013 · Cited by 110
FGF1 — a new weapon to control type 2 diabetes mellitus
Gasser, E., Moutos, C. P., Downes, M., & Evans, R. M. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.78 · Cited by 107
Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels
Shi, L., Bian, X., Qu, Z., Ma, Z., Zhou, Y., Wang, K., Jiang, H., & Xie, J. (2013) · Nature Communications · doi:10.1038/ncomms2439 · Cited by 103
Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin
Davis, K. W., Wellman, P. J., & Clifford, P. S. (2007) · Regulatory Peptides · doi:10.1016/j.regpep.2006.12.003 · Cited by 105
“dopamine activation in the nucleus accumbens [38], suggesting that this neuropeptide is positioned so as to mediate the modulation of reinforcement circuits by FR.”
BackgroundBretault, M., Boillot, A., Muzard, L., Poitou, C., Oppert, J., Barsamian, C., Gatta‐Cherifi, B., Muller, H. L., Weismann, D., Rottembourg, D., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4184 · Cited by 104
“In this regard, it is known that receptors for ghrelin, an orexigenic gut hormone that is believed important for appetite, are found in various regions, including the brainstem and midbrain (34, 35), which would not predictably be damaged by treatment of a tumor located in the sellar or parasellar region.”
Ultra-Processed Food, Reward System and Childhood Obesity
Calcaterra, V., Cena, H., Rossi, V., Santero, S., Bianchi, A., & Zuccotti, G. (2023) · Children · doi:10.3390/children10050804 · Cited by 129
“Human studies also show that leptin can control reward responses [101,102].”
BackgroundHeterogeneity of Ghrelin/Growth Hormone Secretagogue Receptors
Muccioli, G., Baragli, A., Granata, R., Papotti, M., & Ghigo, E. (2007) · Neuroendocrinology · doi:10.1159/000105141 · Cited by 104
Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats
Zheng, J., Babygirija, R., Bülbül, M., Cerjak, D., Ludwig, K., & Takahashi, T. (2010) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00483.2009 · Cited by 104
Brown, J. A., Woodworth, H. L., & Leinninger, G. M. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00009 · Cited by 106
“…of OX signaling (but presumably leaving other releasable transmitters in OX neurons intact) inhibits DA release to the NA and operant responding for drugs, food or sucrose (Abizaid et al., 2006; España et al., 2010; Sharf et al., 2010; Smith and Aston-Jones, 2012; Srinivasan et al., 2012).”
BackgroundGhrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus
Ribeiro, L. F., Catarino, T., Santos, S. D., Benoist, M., van Leeuwen, J. F., Esteban, J. A., & Carvalho, A. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1313798111 · Cited by 101
“In addition to inducing a robust feeding response through its hypothalamic action, ghrelin affects other feeding-related behaviors including olfactory function (56), motivational aspects of feeding (57, 58), and hippocampal memory retention (6, 15–17, 43, 59).”
BackgroundThe Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior
Anderberg, R. H., Hansson, C., Fenander, M., Richard, J. E., Dickson, S. L., Nissbrandt, H., Bergquist, F., & Skibicka, K. P. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.297 · Cited by 114
“…are consistent with several previous studies showing that ghrelin activation of the VTA dopamine neurons increases dopamine release in the NAc (Abizaid et al, 2006; Jerlhag et al, 2007; Abizaid, 2009), dopamine production in the VTA, and increased electrical activity of the VTA dopamine…”
Regulation of the mesolimbic dopamine circuit by feeding peptides
Liu, S., & Borgland, S. L. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.12.046 · Cited by 104
Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system
Jerlhag, E., Egecioglu, E., Dickson, S. L., & Engel, J. A. (2010) · Addiction Biology · doi:10.1111/j.1369-1600.2010.00231.x · Cited by 102
“Previously, a role for NMDA, opioid as well as orexin A receptors in different aspects of ghrelininduced activation of the mesolimbic dopamine systems has been suggested (Toshinai et al. 2003; Naleid et al. 2005; Abizaid et al. 2006).”
BackgroundInfluentialCottone, P., Sabino, V., Steardo, L., & Zorrilla, E. P. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.08.010 · Cited by 104
“Mechanistic mediators might include leptin, ghrelin or other energy homeostasis hormones that directly modulate reward neurocircuitry (Abizaid et al., 2006; Cota et al., 2006).”
BackgroundHansson, C., Haage, D., Taube, M., Egecioglu, E., Salomé, N., & Dickson, S. L. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.02.002 · Cited by 105
“This dose was selected based on previous electrophysiological studies of ghrelin-responsive neurons in other brain areas (Bajic et al., 2004; Abizaid et al., 2006).”
Unger, M. M., Möller, J. C., Mankel, K., Eggert, K. M., Bohne, K., Bodden, M., Stiasny-Kolster, K., Kann, P. H., Mayer, G., Tebbe, J. J., et al. (2011) · Journal of Neurology · doi:10.1007/s00415-010-5864-1 · Cited by 97
“In addition, ghrelin acts on higher brain functions [1, 15].”
BackgroundJerlhag, E., Landgren, S., Egecioglu, E., Dickson, S. L., & Engel, J. A. (2010) · Alcohol · doi:10.1016/j.alcohol.2010.10.002 · Cited by 101
“This gutebrain hormone also plays a role in brain reward and food-seeking behavior (Abizaid et al., 2006; Egecioglu et al., 2010; Jerlhag, 2008; Jerlhag et al., 2006, 2007, 2008; Naleid et al., 2005).”
BackgroundGastric Mammalian Target of Rapamycin Signaling Regulates Ghrelin Production and Food Intake
Xu, G., Li, Y., An, W., Li, S., Guan, Y., Wang, N., Tang, C., Wang, X., Zhu, Y., Li, X., et al. (2009) · Endocrinology · doi:10.1210/en.2009-0372 · Cited by 98
Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain
Perelló, M., Scott, M. M., Sakata, I., Lee, C. E., Chuang, J.-C., Osborne-Lawrence, S. L., Rovinsky, S. A., Elmquist, J. K., & Zigman, J. M. (2011) · The Journal of Comparative Neurology · doi:10.1002/cne.22690 · Cited by 99
Patterson, Z. R., Ducharme, R., Anisman, H., & Abizaid, A. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07310.x · Cited by 95
“Peripheral injections and local ghrelin infusions into the VTA produce DA release in mice and rats, an effect that is absent in GHSR KO mice (Abizaid et al., 2006; Jiang et al., 2006; Jerlhag et al., 2007; Jerlhag, 2008).”
BackgroundResultInfluentialSelf-citationSuchankova, P., Steensland, P., Fredriksson, I., Engel, J. A., & Jerlhag, E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071284 · Cited by 95
“activates the mesocorticolimbic dopamine system [18–22] and that”
BackgroundPeptide drugs to target G protein-coupled receptors
Bellmann‐Sickert, K., & Beck‐Sickinger, A. G. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.06.003 · Cited by 95
Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward
Schellekens, H., Dinan, T. G., & Cryan, J. F. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00148 · Cited by 96
“For example, dopaminergic cells in the VTA are sensitive to ghrelin, as well as noradrenergic cells in the NTS in the brainstem and serotinergic cells in the midbrain raphe nuclei (Carlini et al., 2004; Abizaid et al., 2006; Date et al., 2006).”
BackgroundKoopmann, A., von der Goltz, C., Grosshans, M., Dinter, C., Vitale, M., Wiedemann, K., & Kiefer, F. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.11.005 · Cited by 94
“In one such study, Abizaid et al. (2006) showed ghrelin to stimulate, through its effect on GHS-R1A receptors, the firing rate of dopaminergic neurons in the VTA.”
InfluentialGut-brain axis and addictive disorders: A review with focus on alcohol and drugs of abuse
Jerlhag, E. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.11.005 · Cited by 92
Ghrelin increases the motivation to eat, but does not alter food palatability
Overduin, J., Figlewicz, D. P., Jay, J. L., Kittleson, S., & Cummings, D. E. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00488.2011 · Cited by 93
Holliday, N. D., Holst, B., Rodionova, E., Schwartz, T. W., & Cox, H. M. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0254 · Cited by 92
The Central Nervous System Sites Mediating the Orexigenic Actions of Ghrelin
Mason, B. L., Wang, Q., & Zigman, J. M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170310 · Cited by 89
“Receptors for ghrelin are highly expressed in the VTA and the substantia nigra (40, 44, 55) within both dopaminergic (THimmunoreactive) neurons (40, 44) and GABAergic neurons (44).”
Background
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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