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| Status |
Public on Sep 10, 2019 |
| Title |
Habenular Tcf7l2 links nicotine addiction to diabetes |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Nicotine contained in tobacco smoke increases blood glucose levels in humans, and the risk of developing diabetes is dramatically increased in habitual smokers. Little is currently known about how nicotine increases blood glucose levels or the relevance of this action to either the persistence of the smoking habit or the pathophysiology of diabetes in smokers. Here, we show that the diabetes-associated gene Tcf7l2 is highly expressed in the medial habenula (mHb), where it regulates the function of local nicotinic acetylcholine receptors. We find that Tcf7l2 mutant (Tcf7l2mut) rats consume far greater quantities of nicotine than wild-type rats. Similarly, CRISPR-mediated cleavage of wild-type Tcf7l2 in the mHb increases nicotine intake in mice. Polysynaptic tracing identified a connection from the mHb to the pancreas, and nicotine-induced activation of the mHb elevates blood glucose. This effect is mimicked by chemogenetic stimulation of the mHb and blocked by Tcf7l2 knockdown in mHb. A history of nicotine consumption elevates circulating levels of the pancreas-derived hormones glucagon and insulin and precipitates diabetes-like dysregulation of blood glucose homeostasis in wild-type rats, whereas Tcf7l2mut rats are resistant to these actions of nicotine. Our findings suggest that Tcf7l2 regulates the stimulatory actions of nicotine on the habenula-pancreas axis, linkings the addictive properties of nicotine to its diabetes-promoting actions.
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| Overall design |
RNA-Seq is performed in three brain regions, including medial habenula (mHb), Interpeduncular nuclear (IPn) and dorsal hippocampus (dHIP), from wild-type and Tcf7l2 mutant rats.
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| Contributor(s) |
Duncan A, Wang Z, Ma'ayan A, Kenny PJ |
| Citation(s) |
31619789 |
| Submission date |
Sep 09, 2019 |
| Last update date |
Oct 18, 2019 |
| Contact name |
Zichen Wang |
| E-mail(s) |
zichen.wang@mssm.edu
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| Organization name |
Icahn School of Medicine at Mount Sinai
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| Department |
Pharmacological Sciences
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| Lab |
Avi Ma'ayan
|
| Street address |
1468 Madison Ave
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (1) |
| GPL18694 |
Illumina HiSeq 2500 (Rattus norvegicus) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA564583 |
| SRA |
SRP221065 |
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