Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding

Hommel, Jonathan D.; Trinko, Richard; Sears, Robert M.; Georgescu, Dan; Liu, Zong-Wu; Gao, Xiao-Bing; Thurmon, Jeremy J.; Marinelli, Michela; DiLeone, Ralph J.

doi:10.1016/j.neuron.2006.08.023

Cited by 902Regulation of Appetite and ObesityNeurotransmitter Receptor Influence on BehaviorHypothalamic control of reproductive hormones

Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding

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Hommel, Jonathan D., Trinko, Richard, Sears, Robert M., Georgescu, Dan, Liu, Zong-Wu, Gao, Xiao-Bing, Thurmon, Jeremy J., Marinelli, Michela +1 more·2006·Neuron

DOI 10.1016/j.neuron.2006.08.023

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Abstract

The leptin hormone is critical for normal food intake and metabolism. While leptin receptor (Lepr) function has been well studied in the hypothalamus, the functional relevance of Lepr expression in the ventral tegmental area (VTA) has not been investigated. The VTA contains dopamine neurons that are important in modulating motivated behavior, addiction, and reward. Here, we show that VTA dopamine neurons express Lepr mRNA and respond to leptin with activation of an intracellular JAK-STAT pathway and a reduction in firing rate. Direct administration of leptin to the VTA caused decreased food intake while long-term RNAi-mediated knockdown of Lepr in the VTA led to increased food intake, locomotor activity, and sensitivity to highly palatable food. These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons.

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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 [84]
Leptin injections into the VTA decreased dopamine neuron activity and acutely suppressed food intake, while adenoviral knockdown of leptin receptors specifically in the VTA resulted in increased sucrose preference and sustained palatable food intake.
“other studies demonstrated that such leptin injections decreased dopamine neuron activity and acutely suppressed food intake, while adenoviral knockdown of leptin receptors specifically in the ventral tegmental area (VTA) resulted in increased sucrose preference and sustained palatable food intake ([84](#B84))”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [84]
Leptin signaling has important modulatory effects on dopaminergic neurons that are part of reward pathways that provide input to the nucleus accumbens.
“It has recently become clear, however, that leptin signaling has important modulatory effects on dopaminergic neurons that are part of reward pathways that provide input to the nucleus accumbens (50,51).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [51]

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Authors: Hommel, J. D., Trinko, R., Sears, R. M., Georgescu, D., Liu, Z.-W., Gao, X.-B., Thurmon, J. J., Marinelli, M., & DiLeone, R. J.
Affiliations: The University of Texas Southwestern Medical Center (US)
Yale University (US)
Hubei University of Medicine (CN)
Rosalind Franklin University of Medicine and Science (US)
Corresponding author: DiLeone, Ralph J.
ORCID: Hommel, Jonathan D.
Trinko, Richard
Sears, Robert M.
Gao, Xiao-Bing
Marinelli, Michela
DiLeone, Ralph J.
Venue: Neuron
Publisher: Elsevier BV
Published: 2006-09
Volume: 51
Issue: 6
Pages: 801-810
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2006.08.023
OpenAlex: W1977915489
Cited by: 902
References: 61
Citations by year: 2026: 9 · 2025: 26 · 2024: 21 · 2023: 33 · 2022: 38 · 2021: 35 · 2020: 36 · 2019: 34 · 2018: 48 · 2017: 55 · 2016: 45 · 2015: 57 · 2014: 63 · 2013: 59 · 2012: 58
FWCI: 21.01
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: National Institutes of Health (DK071205)
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: leptin, leptin receptor, ventral tegmental area, dopaminergic neurons, feeding behavior, dietary intake, JAK/STAT signaling, locomotor activity, palatability, reward, RNAi knockdown
MeSH terms: Action Potentials, Animals, Dopamine, Eating, Feeding Behavior, Infusions, Intravenous, Mesencephalon, Mice, Inbred C57BL, Motor Activity, Neurons, Phosphorylation, Receptors, Cell Surface, RNA, Messenger, Signal Transduction, Gene Expression, Rats, Sprague-Dawley, In Situ Hybridization, Fluorescence, Ventral Tegmental Area, Leptin, RNA Interference, STAT3 Transcription Factor, Mice, Rats, Receptors, Leptin, In Vitro Techniques

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Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding

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