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Nature. 2019 Oct;574(7778):372-377. doi: 10.1038/s41586-019-1653-x. Epub 2019 Oct 16.

Habenular TCF7L2 links nicotine addiction to diabetes.

Author information

1
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, Jupiter, FL, USA.
3
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, Shenzhen, China.
4
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA.
6
Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
7
The Laboratory of Molecular Biology, The Rockefeller University, New York, NY, USA.
8
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
9
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. paul.kenny@mssm.edu.

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.

PMID:
31619789
DOI:
10.1038/s41586-019-1653-x

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