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; Paul J. Kenny

doi:10.1038/s41586-019-1653-x

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-TallonAron M. Geurts, Paul J. Kenny

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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.

Original language	English
Pages (from-to)	372-377
Number of pages	6
Journal	Nature
Volume	574
Issue number	7778
DOIs	https://doi.org/10.1038/s41586-019-1653-x
State	Published - 17 Oct 2019

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Duncan, A., Heyer, M. P., Ishikawa, M., Caligiuri, S. P. B., Liu, X. A., Chen, Z., Vittoria Micioni Di Bonaventura, M., 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., ... Kenny, P. J. (2019). Habenular TCF7L2 links nicotine addiction to diabetes. Nature, 574(7778), 372-377. https://doi.org/10.1038/s41586-019-1653-x

@article{511c608b8e8a4c5892d3c0904030397e,

title = "Habenular TCF7L2 links nicotine addiction to diabetes",

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.",

author = "Alexander Duncan and Heyer, {Mary P.} and Masago Ishikawa and Caligiuri, {Stephanie P.B.} and Liu, {Xin an} and Zuxin Chen and {Vittoria Micioni Di Bonaventura}, Maria and Elayouby, {Karim S.} and Ables, {Jessica L.} and Howe, {William M.} and Purva Bali and Clementine Fillinger and Maya Williams and O{\textquoteright}Connor, {Richard M.} and Zichen Wang and Qun Lu and Kamenecka, {Theodore M.} and Avi Ma{\textquoteright}ayan and O{\textquoteright}Neill, {Heidi C.} and Ines Ibanez-Tallon and Geurts, {Aron M.} and Kenny, {Paul J.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = oct,

day = "17",

doi = "10.1038/s41586-019-1653-x",

language = "English",

volume = "574",

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Duncan, A, Heyer, MP, Ishikawa, M, Caligiuri, SPB, Liu, XA, Chen, Z, Vittoria Micioni Di Bonaventura, M, Elayouby, KS, Ables, JL, Howe, WM, Bali, P, Fillinger, C, Williams, M, O’Connor, RM, Wang, Z, Lu, Q, Kamenecka, TM, Ma’ayan, A, O’Neill, HC, Ibanez-Tallon, I, Geurts, AM & Kenny, PJ 2019, 'Habenular TCF7L2 links nicotine addiction to diabetes', Nature, vol. 574, no. 7778, pp. 372-377. https://doi.org/10.1038/s41586-019-1653-x

TY - JOUR

T1 - Habenular TCF7L2 links nicotine addiction to diabetes

AU - Duncan, Alexander

AU - Heyer, Mary P.

AU - Ishikawa, Masago

AU - Caligiuri, Stephanie P.B.

AU - Liu, Xin an

AU - Chen, Zuxin

AU - Vittoria Micioni Di Bonaventura, Maria

AU - Elayouby, Karim S.

AU - Ables, Jessica L.

AU - Howe, William M.

AU - Bali, Purva

AU - Fillinger, Clementine

AU - Williams, Maya

AU - O’Connor, Richard M.

AU - Wang, Zichen

AU - Lu, Qun

AU - Kamenecka, Theodore M.

AU - Ma’ayan, Avi

AU - O’Neill, Heidi C.

AU - Ibanez-Tallon, Ines

AU - Geurts, Aron M.

AU - Kenny, Paul J.

PY - 2019/10/17

Y1 - 2019/10/17

N2 - 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.

AB - 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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U2 - 10.1038/s41586-019-1653-x

DO - 10.1038/s41586-019-1653-x

M3 - Article

C2 - 31619789

AN - SCOPUS:85073431118

SN - 0028-0836

VL - 574

SP - 372

EP - 377

JO - Nature

JF - Nature

IS - 7778

ER -

Habenular TCF7L2 links nicotine addiction to diabetes

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