Journal Article

Habenular TCF7L2 links nicotine addiction to diabetes

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

2019

Overview

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. The transcription factor TCF7L2 mediates two important responses to nicotine in the medial habenula region of the rodent brain: aversion to nicotine, and regulation of blood sugar levels through a polysynaptic habenula–pancreas circuit.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 14 / 38 / 38/91 / 42 / 42/89 / 45 / 59 / 59/36 / 631/378/1788 / 631/378/1959/1315 / 631/443/319 / 9/74 / Acetylcholine receptors (nicotinic) / Addictions / Animals / Bioinformatics / Blood / Blood circulation / Blood glucose / Cyclic AMP - metabolism / Diabetes / Diabetes mellitus / Glucagon / Glucose / Glucose - metabolism / Glucose Metabolism Disorders - genetics / Glucose Metabolism Disorders - metabolism / Habenula / Habenula - metabolism / Health aspects / Homeostasis / Humanities and Social Sciences / Humans / Insulin / Kinases / Mice / multidisciplinary / Mutagenesis / Neurons / Nicotine / Nicotine - metabolism / Pancreas / Pancreas - metabolism / PC12 Cells / Phosphorylation / Physiological aspects / Proteins / Rats / Receptor mechanisms / Receptors / Receptors, Nicotinic - metabolism / Risk factors / Science / Science (multidisciplinary) / Signal Transduction / Smoking / Tobacco / Tobacco Use Disorder - complications / Tobacco Use Disorder - genetics / Tobacco Use Disorder - metabolism / Transcription Factor 7-Like 2 Protein - genetics / Transcription Factor 7-Like 2 Protein - metabolism / Transcription factors / Viruses