Cell Metabolism
Volume 22, Issue 4, 6 October 2015, Pages 741-749
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Short Article
Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons

https://doi.org/10.1016/j.cmet.2015.08.003Get rights and content
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Highlights

  • Dopamine-specific STAT3 knockout increases locomotion and voluntary running

  • Loss of STAT3 in dopamine neurons enhances the rewarding effects of running

  • Intra-VTA leptin inhibits running reward in a manner that relies on STAT3 signaling

  • Loss of STAT3 in dopamine neurons blunts mesolimbic dopamine overflow and function

Summary

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.

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