Leptin Acts via Leptin Receptor-Expressing Lateral Hypothalamic Neurons to Modulate the Mesolimbic Dopamine System and Suppress Feeding
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The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone leptin modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system.
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Leptin receptors are located in hypothalamic areas beyond the arcuate nucleus, including the ventromedial, dorsomedial, premammillary, lateral, and perifornical areas, where they likely contribute to leptin's effects on food intake and energy expenditure.
“But clearly, leptin receptors are located in other hypothalamic areas such as the ventromedial, dorsomedial, and premammillary nuclei, as well as the lateral and perifornical areas where they likely contribute to leptin's effects on food intake and energy expenditure”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [101]
Lateral hypothalamic neurons expressing orexin and other transmitters such as neurotensin provide modulatory input to midbrain dopamine neurons.
“Recent investigations show that lateral hypothalamic neurons expressing orexin ([77](#B77), [199](#B199)) and other transmitters such as neurotensin ([101](#B101), [107](#B107)) provide modulatory input to midbrain dopamine neurons”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [101]
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Hormone Interactions Regulating Energy Balance During Pregnancy
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Feelings about food: the ventral tegmental area in food reward and emotional eating
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Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells
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Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons
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Obesity and the Neurocognitive Basis of Food Reward and the Control of Intake
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Leptin and the systems neuroscience of meal size control
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Putting desire on a budget: dopamine and energy expenditure, reconciling reward and resources
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Sex hormone activity in alcohol addiction: Integrating organizational and activational effects
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Physiology of the orexinergic/hypocretinergic system: a revisit in 2012
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Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back
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Homeostatic and non-homeostatic controls of feeding behavior: Distinct vs. common neural systems
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Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors
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Dopamine, behavior, and addiction
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Self-citationGoforth, P. B., Leinninger, G. M., Patterson, C. M., Satin, L. S., & Myers, M. G. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.5167-13.2014 · Cited by 123 · see citing works
Self-citationTo eat or to sleep: That is a lateral hypothalamic question
Arrigoni, E., Chee, M. J. S., & Fuller, P. M. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.11.017 · Cited by 124 · see citing works
The neural addiction of cancer
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The role of the endocannabinoid system in the neuroendocrine regulation of energy balance
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Direct Innervation and Modulation of Orexin Neurons by Lateral Hypothalamic LepRb Neurons
Louis, G. W., Leinninger, G. M., Rhodes, C. J., & Myers, M. G. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1340-10.2010 · Cited by 115 · see citing works
Self-citationThe Melanin-Concentrating Hormone as an Integrative Peptide Driving Motivated Behaviors
Diniz, G. B., & Bittencourt, J. C. (2017) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2017.00032 · Cited by 115 · see citing works
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Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention
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Anhedonia in depression symptomatology: appetite dysregulation and defective brain reward processing
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Modulation of the mesolimbic dopamine system by leptin
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Self-citationClément, O., Sapin, E., Libourel, P., Arthaud, S., Brischoux, F., Fort, P., & Luppi, P. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1885-12.2012 · Cited by 109 · see citing works
Glutamate and GABA in lateral hypothalamic mechanisms controlling food intake
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Lateral hypothalamus as a sensor-regulator in respiratory and metabolic control
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Profound and redundant functions of arcuate neurons in obesity development
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Local network regulation of orexin neurons in the lateral hypothalamus
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Brown, J. A., Woodworth, H. L., & Leinninger, G. M. (2015) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2015.00009 · Cited by 100 · see citing works
Self-citationRegulation of the mesolimbic dopamine circuit by feeding peptides
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The LepR-mediated leptin transport across brain barriers controls food reward
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The Novel Perspectives of Adipokines on Brain Health
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Leptin modulates nutrient reward via inhibitory galanin action on orexin neurons
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Self-citationFTO genotype impacts food intake and corticolimbic activation
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Neurobiology of overeating and obesity: The role of melanocortins and beyond
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Ghrelin increases the motivation to eat, but does not alter food palatability
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Integration of Satiety Signals by the Central Nervous System
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Self-citation
- Authors
- Leinninger, G. M., Jo, Y.-H., Leshan, R. L., Louis, G. W., Yang, H., Barrera, J. G., Wilson, H., Opland, D. M., Faouzi, M. A., Gong, Y., Jones, J. C., Rhodes, C. J., Chua, S., Diano, S., Horvath, T. L., Seeley, R. J., Becker, J. B., Münzberg, H., & Myers, M. G.
- Affiliations
- University of Michigan (US)
- Albert Einstein College of Medicine (US)
- University of Cincinnati (US)
- University of Chicago (US)
- Yale University (US)
- Corresponding author
- Myers, Martin G.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 10
- Issue
- 2
- Pages
- 89-98
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC2723060
- OpenAlex
- W2001980298
- Cited by
- 412
- References
- 47
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 12 · 2023: 22 · 2022: 16 · 2021: 27 · 2020: 18 · 2019: 19 · 2018: 32 · 2017: 32 · 2016: 30 · 2015: 30 · 2014: 25 · 2013: 33 · 2012: 27
- FWCI
- 14.97
- 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, 1446 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
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Diabetes Research and Training Center
- American Diabetes Association
- American Heart Association
- National Institutes of Health
- Obesity Society
- 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, lateral hypothalamus, ventral tegmental area, mesolimbic dopamine system, feeding behavior, anorexia, inhibitory neurons, dopamine synthesis, body weight regulation, leptin deficiency
- MeSH terms
- Animals, Body Weight, Dopamine, Eating, Hypothalamic Area, Lateral, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Ventral Tegmental Area, Leptin, Mice, Receptors, Leptin, Gene Knock-In Techniques
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