Habenular Tcf7l2 links nicotine addiction to diabetes

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.烟草烟雾中的尼古丁可升高人体血糖水平，习惯性吸烟者罹患糖尿病的风险显著升高。目前学界对于尼古丁升高血糖的具体机制，以及该作用与吸烟成瘾维持、吸烟者糖尿病病理生理学之间的关联尚不清楚。本研究发现，糖尿病相关基因Tcf7l2在内侧缰核（medial habenula，mHb）中高表达，并可调控局部烟碱型乙酰胆碱受体（nicotinic acetylcholine receptors）的功能。研究显示，Tcf7l2突变型（Tcf7l2mut）大鼠的尼古丁摄入量远高于野生型大鼠。同样地，在小鼠内侧缰核中通过CRISPR介导切割野生型Tcf7l2，可增加小鼠的尼古丁摄入。多突触示踪（polysynaptic tracing）技术证实，内侧缰核与胰腺之间存在神经连接；尼古丁诱导的内侧缰核激活可升高血糖水平。该效应可通过化学遗传学刺激（chemogenetic stimulation）内侧缰核得以重现，而在内侧缰核中敲低Tcf7l2则可阻断该效应。野生型大鼠经尼古丁暴露后，循环中胰腺来源的胰高血糖素（glucagon）与胰岛素（insulin）水平会升高，并诱发类糖尿病的血糖稳态失调；而Tcf7l2突变型大鼠对尼古丁的上述作用具有抵抗性。本研究结果表明，Tcf7l2可调控尼古丁对缰核-胰腺轴的刺激作用，从而将尼古丁的成瘾特性与其促糖尿病效应关联起来。