Habenular TCF7L2 links nicotine addiction to diabetes

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. Howe, Purva Bali, Clementine Fillinger, Maya Williams, Richard M. O’Connor, Zichen Wang, Qun Lu, Theodore M. Kamenecka, Avi Ma’ayan, Heidi C. O’Neill, Ines Ibanez-Tallon, Aron M. Geurts and Paul J. Kenny ()
Additional contact information
Alexander Duncan: Icahn School of Medicine at Mount Sinai
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
Zuxin Chen: Icahn School of Medicine at Mount Sinai
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

Nature, 2019, vol. 574, issue 7778, 372-377

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1653-x

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