You have full access to this article via your institution. Download PDF Tobacco smoking is a leading cause of disease and premature death. Even in nonsmokers the tobacco habit can be deadly,

with over 880,000 people worldwide estimated to die each year from diseases related to secondhand smoke exposure [1]. As might be expected, the tobacco habit is associated with diseases of

the respiratory system, including lung cancer, chronic obstructive pulmonary disease (COPD), and asthma. Tobacco smoking also contributes to non-respiratory system diseases. Notably, the

risk of type 2 diabetes (T2D) is much higher in current than former or never smokers. How tobacco smoking contributes to T2D has been unclear but was thought to reflect actions of nicotine

a core component of the signaling cascade associated with glucagon-like peptide-1 (GLP-1). GLP-1 is an incretin hormone that acts on the pancreas to enhance insulin secretion. GLP-1 also

acts on mHb neurons to promote nicotine avoidance [4]. Recently, our laboratory established that doses of nicotine that activate the mHb markedly elevate blood glucose levels in male and

female rodents [3]. CRISPR-mediated genomic cleavage of _Tcf7l2_ in the mHb abolishes the hyperglycemic actions of nicotine and dramatically increases nicotine intake [3]. The stimulatory

effects of nicotine on the mHb are greatly attenuated in genetically modified rats that express a truncated form of TCF7L2 that cannot be activated by GLP-1 [3], which reflects deficits in

TCF7L2-mediated recovery of nAChRs from nicotine-induced desensitization. Chronic nicotine treatment disrupts blood glucose homeostasis in wild-type rats, reflected by elevated fasting blood

glucose and glucagon levels, and TCF7L2 mutant rats are resistant to this action of nicotine [3]. Virus-tracing experiments identified a polysynaptic connection from mHb to the pancreas,

via the autonomic nervous system (ANS), providing a mechanism by which the mHb can influence blood glucose homeostasis [3]. These findings suggest that nicotine elevates blood glucose and

confers risk of T2D through TCF7L2-dependent actions on the mHb. More broadly, these findings suggest that TCF7L2 regulates a habenula–pancreas axis that links the addictive-relevant

behavioral actions of nicotine to its diabetes-promoting actions. That nicotine in cigarettes, vaping devices or transdermal patches can act on the habenula to modulate ANS control of

pancreas, and likely other organ systems, has important implications for our understanding of the etiology of tobacco-related diseases. For example, T2D and other diseases associated with

ANS dysfunction in smokers and nonsmokers could reflect abnormalities in brain–body interactions [5]. If so, novel therapeutics designed to modulate brain–body communication could be used to

treat T2D and other smoking-related diseases. By extension, currently available diabetes therapeutics could potentially exert some of their beneficial effects through actions in the brain

[6]. Another important consideration is whether organ systems and physiological processes outside the brain that are impacted by nicotine, such as maintenance of blood glucose levels, can in

turn modulate the function of brain circuits involved in reward and motivation. If so, peripheral organs may play a previously unrecognized role in the etiology of tobacco dependence and

other substance use disorders. Ultimately, as our understanding of brain–body interactions increases, it may be necessary to broaden brain-centric conceptualizations of drug addiction to

encompass the notion of “whole-body” perturbations. FUNDING AND DISCLOSURE This work was supported by grants from the National Institute on Drug Abuse (NIDA) to PJK (DA020686 and DA045649)

and by the Canadian Institutes of Health Research Post-Doctoral Fellowship (to SPBC). PJK holds equity in Eolas Therapeutics Inc. SPBC declares no competing interests. REFERENCES * Oberg M,

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AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA Stephanie P. B. Caligiuri & Paul

J. Kenny Authors * Stephanie P. B. Caligiuri View author publications You can also search for this author inPubMed Google Scholar * Paul J. Kenny View author publications You can also search

for this author inPubMed Google Scholar CONTRIBUTIONS SPBC and PJK wrote the paper. CORRESPONDING AUTHOR Correspondence to Paul J. Kenny. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer

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ARTICLE Caligiuri, S.P.B., Kenny, P.J. Habenular TCF7L2 links nicotine addiction to diabetes: the broad significance. _Neuropsychopharmacol._ 46, 267–268 (2021).

https://doi.org/10.1038/s41386-020-00859-6 Download citation * Published: 09 September 2020 * Issue Date: January 2021 * DOI: https://doi.org/10.1038/s41386-020-00859-6 SHARE THIS ARTICLE

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