Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons.
The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food.
Centre de Recherche du CHUM and Montreal Diabetes Research Center, Université de Montreal, QC H2X 0A9, Canada; Department of Physiology, Université de Montreal, QC H2X 0A9, Canada.
Maria Fernanda A
MF
Fernandes
Centre de Recherche du CHUM and Montreal Diabetes Research Center, Université de Montreal, QC H2X 0A9, Canada; Department of Neuroscience, Université de Montreal, QC H2X 0A9, Canada.
Dominique
D
Matthys
Centre de Recherche du CHUM and Montreal Diabetes Research Center, Université de Montreal, QC H2X 0A9, Canada; Department of Physiology, Université de Montreal, QC H2X 0A9, Canada.
Cécile
C
Hryhorczuk
Centre de Recherche du CHUM and Montreal Diabetes Research Center, Université de Montreal, QC H2X 0A9, Canada; Department of Nutrition, Université de Montreal, QC H2X 0A9, Canada.
Sandeep
S
Sharma
Centre de Recherche du CHUM and Montreal Diabetes Research Center, Université de Montreal, QC H2X 0A9, Canada.
Shabana
S
Mogra
Centre de Recherche du CHUM and Montreal Diabetes Research Center, Université de Montreal, QC H2X 0A9, Canada; Department of Medicine, Université de Montreal, QC H2X 0A9, Canada.
Thierry
T
Alquier
Centre de Recherche du CHUM and Montreal Diabetes Research Center, Université de Montreal, QC H2X 0A9, Canada; Department of Nutrition, Université de Montreal, QC H2X 0A9, Canada; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC H4B 1R6, Canada. Electronic address: stephanie.fulton@umontreal.ca.
Stephanie
S
Fulton
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D007150:Immunohistochemistry; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D020738:Leptin; D012333:RNA, Messenger; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor