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Habenular TCF7L2 links nicotine addiction to diabetes
Open accessAbstract
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.
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“Using a line of Tcf7l2 mutant (Tcf7l2 mut ) rats in which the DNA-binding do-main of TCF7L2 was deleted using zinc finger nucleases it was shown that nicotine self-administration behavior is markedly enhanced by TCF7L2 deficiency (Duncan et al. 2019).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Duncan et al. 2019
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“Notably, TCF7L2 is highly enriched in MHb neurons (Duncan et al. 2019).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Duncan et al. 2019
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“Inhibition of TCF7L2 activity in the MHb, accomplished in mice by CRISPR-Cas9 cleavage of Tcf7l2 DNA or in rats by local delivery of short interfering RNAs to knock down Tcf7l2 transcripts, dramatically increases nicotine intake (Duncan et al. 2019).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Duncan et al. 2019
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“Using whole-cell recordings to assess pharmacologically isolated nAChR currents in MHb slices, it was shown that the amplitude of nicotine-evoked nAChR currents were similar in wild-type and TCF7L2-deficent rats (Duncan et al. 2019).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Duncan et al. 2019
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“However, unlike nAChRs in the MHb of wild-type rats, nAChRs failed to recover from nicotine-induced desensitization in TCF7L2deficent rats (Duncan et al. 2019).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Duncan et al. 2019
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Metadata
- Authors
- Duncan, A., Heyer, M. P., Ishikawa, M., Caligiuri, S. P. B., Liu, X.-A., Chen, Z., Micioni Di Bonaventura, M. V., Elayouby, K. S., Ables, J. L., Howe, W. M., Bali, P., Fillinger, C., Williams, M., O’Connor, R. M., Wang, Z., Lu, Q., Kamenecka, T. M., Ma’ayan, A., O’Neill, H. C., Ibanez-Tallon, I., Geurts, A. M., & Kenny, P. J.
- Affiliations
- Scripps Research Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Chinese Academy of Sciences (CN)
- University of Colorado Boulder (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Kenny, Paul J.
- ORCID
- Venue
- Nature
- Published
- 2019-10-16
- Volume
- 574
- Issue
- 7778
- Pages
- 372-377
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9851388
- OpenAlex
- W2980685606
- Cited by
- 119
- References
- 48
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 13 · 2023: 21 · 2022: 18 · 2021: 15 · 2020: 26 · 2019: 6
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Unicam Scientific Publications (University of Camerino) (submittedVersion)
- Funders
- National Institute on Drug Abuse (P30DA035756, DA020686, R01DA020686, DA035756, P01DA047233, R37DA020686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- TCF7L2, nicotine dependence, diabetes mellitus, medial habenula, nicotinic acetylcholine receptors, blood glucose homeostasis, glucagon, insulin, polysynaptic connections, nicotine aversion, smoking
- MeSH terms
- Cyclic AMP, Animals, Glucose, Humans, Nicotine, Pancreas, Receptors, Nicotinic, Tobacco Use Disorder, Signal Transduction, Mutagenesis, PC12 Cells, Habenula, Glucose Metabolism Disorders, Mice, Rats, Transcription Factor 7-Like 2 Protein
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