Diabetes is far more prevalent in smokers than non-smokers, but little is known about underlying mechanisms of vulnerability. Here, we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb), where it regulates the function of nicotinic acetylcholine receptors. Inhibition of Tcf7l2 signaling in the mHb increases nicotine intake in mice and rats. Nicotine elevates blood glucose levels through a Tcf7l2-dependent stimulatory action on the mHb. Virus tracing identifies a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show elevated circulating levels of glucagon and insulin and diabetes-like dysregulation of blood glucose homeostasis. In contrast, Tcf7l2 mut 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.

microRNAs have been implicated in mediating key aspects of skeletal muscle development and responses to diseases and injury. Recently, we demonstrated that a synaptically enriched microRNA, miR-206, functions to promote maintenance and repair of the neuromuscular junction (NMJ); in mutant mice lacking miR-206, reinnervation is impaired following nerve injury and loss of NMJs is accelerated in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we asked whether other microRNAs play similar roles. One attractive candidate is miR-133b because it is in the same transcript that encodes miR-206. Like miR-206, miR-133b is concentrated near NMJs and induced after denervation. In miR-133b null mice, however, NMJ development is unaltered, reinnervation proceeds normally following nerve injury, and disease progression is unaffected in the SOD1(G93A) mouse model of ALS. To determine if miR-206 compensates for the loss of miR-133b, we generated mice lacking both microRNAs. The phenotype of these double mutants resembled that of miR-206 single mutants. Finally, we used conditional mutants of Dicer, an enzyme required for the maturation of most microRNAs, to generate mice in which microRNAs were depleted from skeletal muscle fibers postnatally, thus circumventing a requirement for microRNAs in embryonic muscle development. Reinnervation of muscle fibers following injury was impaired in these mice, but the defect was similar in magnitude to that observed in miR-206 mutants. Together, these results suggest that miR-206 is the major microRNA that regulates repair of the NMJ following nerve injury.