Leptin Regulation of the Mesoaccumbens Dopamine Pathway

Fulton, Stephanie; Pissios, Pavlos; Manchon, Ramon Pinol; Stiles, Linsey; Frank, Lauren; Pothos, Emmanuel N.; Maratos-Flier, Eleftheria; Flier, Jeffrey S.

doi:10.1016/j.neuron.2006.09.006

Cited by 644Regulation of Appetite and ObesityNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Leptin Regulation of the Mesoaccumbens Dopamine Pathway

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Fulton, Stephanie, Pissios, Pavlos, Manchon, Ramon Pinol, Stiles, Linsey, Frank, Lauren, Pothos, Emmanuel N., Maratos-Flier, Eleftheria, Flier, Jeffrey S.·2006·Neuron

DOI 10.1016/j.neuron.2006.09.006

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Abstract

Leptin is an adipose-derived hormone that acts on hypothalamic leptin receptors to regulate energy balance. Leptin receptors are also expressed in extrahypothalamic sites including the ventral tegmental area (VTA), critical to brain reward circuitry. We report that leptin targets DA and GABA neurons of the VTA, inducing phosphorylation of signal-transducer-and-activator-of-transcription-3 (STAT3). Retrograde tracing combined with pSTAT3 immunohistochemistry show leptin-responsive VTA neurons projecting to nucleus accumbens (NAc). Assessing leptin function in the VTA, we showed that ob/ob mice had diminished locomotor response to amphetamine and lacked locomotor sensitization to repeated amphetamine injections, both defects reversed by leptin infusion. Electrically stimulated DA release from NAc shell terminals was markedly reduced in ob/ob slice preparations, and NAc DA levels and TH expression were lower. These data define a role for leptin in mesoaccumbens DA signaling and indicate that the mesoaccumbens DA pathway, critical to integrating motivated behavior, responds to this adipose-derived signal.

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Leptin-deficient mice exhibit suppressed rather than increased dopamine neuron activity, and leptin-replacement therapy restored normal dopamine neuron activity as well as amphetamine-induced locomotor sensitization.
“leptin-deficient mice (absence of leptin-receptor signaling) exhibit suppressed rather than increased dopamine neuron activity [as expected from the viral knockdown experiments in rats ([84](#B84))], and leptin-replacement therapy restored normal dopamine neuron activity as well as amphetamine-induced locomotor sensitization ([63](#B63))”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [63]
Mesolimbic dopamine signaling is severely suppressed in leptin-deficient ob/ob mice and rescued by systemic leptin replacement.
“Mesolimbic dopamine signaling is also severely suppressed in leptin-deficient *ob/ob* mice and rescued by systemic leptin replacement ([63](#B63)).”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [63]

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Authors: Fulton, S., Pissios, P., Manchon, R. P., Stiles, L., Frank, L., Pothos, E. N., Maratos-Flier, E., & Flier, J. S.
Affiliations: Beth Israel Deaconess Medical Center (US)
Tufts University (US)
Corresponding author: Flier, Jeffrey S.
ORCID: Fulton, Stephanie
Stiles, Linsey
Pothos, Emmanuel N.
Flier, Jeffrey S.
Venue: Neuron
Publisher: Elsevier BV
Published: 2006-09
Volume: 51
Issue: 6
Pages: 811-822
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2006.09.006
OpenAlex: W2050684182
Cited by: 644
References: 60
Citations by year: 2026: 5 · 2025: 19 · 2024: 18 · 2023: 18 · 2022: 20 · 2021: 32 · 2020: 19 · 2019: 26 · 2018: 27 · 2017: 39 · 2016: 30 · 2015: 45 · 2014: 35 · 2013: 43 · 2012: 40
FWCI: 17.51
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2511 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research
National Institutes of Health (DKR37 28082)
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
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: leptin, ventral tegmental area, nucleus accumbens, STAT3 phosphorylation, dopaminergic neurons, GABAergic neurons, ob/ob mice, locomotor sensitization, dopamine release, reward systems, energy balance
MeSH terms: Amphetamine, Central Nervous System Stimulants, Analysis of Variance, Animals, Dopamine, Drug Synergism, Immunohistochemistry, Mice, Obese, Neurons, Nucleus Accumbens, Phosphorylation, Receptors, Cell Surface, Tyrosine 3-Monooxygenase, Signal Transduction, Ventral Tegmental Area, Mice, Knockout, Microscopy, Confocal, Leptin, STAT3 Transcription Factor, Mice, Receptors, Leptin

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Leptin Regulation of the Mesoaccumbens Dopamine Pathway

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