Leptin receptor signaling in midbrain dopamine neurons regulates feeding.
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.
Hommel
Jonathan D
JD
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Trinko
Richard
R
Sears
Robert M
RM
Georgescu
Dan
D
Liu
Zong-Wu
ZW
Gao
Xiao-Bing
XB
Thurmon
Jeremy J
JJ
Marinelli
Michela
M
DiLeone
Ralph J
RJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism
D020738:Leptin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C515447:leptin receptor, mouse; D004298:Dopamine