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Habenular TCF7L2 links nicotine addiction to diabetes

Author

Listed:
  • Alexander Duncan

    (Icahn School of Medicine at Mount Sinai
    Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research)

  • Mary P. Heyer

    (Icahn School of Medicine at Mount Sinai)

  • Masago Ishikawa

    (Icahn School of Medicine at Mount Sinai)

  • Stephanie P. B. Caligiuri

    (Icahn School of Medicine at Mount Sinai)

  • Xin-an Liu

    (Icahn School of Medicine at Mount Sinai
    Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions)

  • Zuxin Chen

    (Icahn School of Medicine at Mount Sinai
    Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions)

  • Maria Vittoria Micioni Di Bonaventura

    (Icahn School of Medicine at Mount Sinai)

  • Karim S. Elayouby

    (Icahn School of Medicine at Mount Sinai)

  • Jessica L. Ables

    (Icahn School of Medicine at Mount Sinai)

  • William M. Howe

    (Icahn School of Medicine at Mount Sinai)

  • Purva Bali

    (Icahn School of Medicine at Mount Sinai)

  • Clementine Fillinger

    (Icahn School of Medicine at Mount Sinai)

  • Maya Williams

    (Icahn School of Medicine at Mount Sinai)

  • Richard M. O’Connor

    (Icahn School of Medicine at Mount Sinai)

  • Zichen Wang

    (Icahn School of Medicine at Mount Sinai)

  • Qun Lu

    (The Scripps Research Institute)

  • Theodore M. Kamenecka

    (The Scripps Research Institute)

  • Avi Ma’ayan

    (Icahn School of Medicine at Mount Sinai)

  • Heidi C. O’Neill

    (University of Colorado)

  • Ines Ibanez-Tallon

    (The Rockefeller University)

  • Aron M. Geurts

    (Medical College of Wisconsin)

  • Paul J. Kenny

    (Icahn School of Medicine at Mount Sinai)

Abstract

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula–pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Suggested Citation

  • Alexander Duncan & Mary P. Heyer & Masago Ishikawa & Stephanie P. B. Caligiuri & Xin-an Liu & Zuxin Chen & Maria Vittoria Micioni Di Bonaventura & Karim S. Elayouby & Jessica L. Ables & William M. How, 2019. "Habenular TCF7L2 links nicotine addiction to diabetes," Nature, Nature, vol. 574(7778), pages 372-377, October.
    • Handle: RePEc:nat:nature:v:574:y:2019:i:7778:d:10.1038_s41586-019-1653-x
    DOI: 10.1038/s41586-019-1653-x
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    Cited by:

    1. Liang Yang & Junfeng Shen & Chunhua Liu & Zhonghua Kuang & Yong Tang & Zhengjiang Qian & Min Guan & Yongfeng Yang & Yang Zhan & Nan Li & Xiang Li, 2023. "Nicotine rebalances NAD+ homeostasis and improves aging-related symptoms in male mice by enhancing NAMPT activity," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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