Habenular TCF7L2 links nicotine addiction to diabetes

Abstract

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.

The habenular G-protein–coupled receptor 151 regulates synaptic plasticity and nicotine intake

“…Interestingly, UK biobank studies have recently shown that GPR151 loss-of-function alleles are associated with lower body mass index and protection from diabetes type 2 (44). Related to this, we have recently found that nicotine acts on MHb neurons, which are polysynaptically connected to the pancreas, to stimulate increases in blood glucose levels, and prolonged exposure to this action of nicotine can precipitate the emergence of diabetes in laboratory rodents (39). This suggests that GPR151 may influence diabetes vulnerability, particularly in smokers, by regulating MHb function.…”

“…Phosphorylation by cAMP-dependent kinases regulates the rate of desensitization of nAChRs (38), and specific PKA phosphorylation sites are modulated differently by acute or chronic exposure to nicotine (36,37). It has also been shown that deficits in cAMP signaling can alter nicotine intake in mice (39). Given our demonstration that loss of Gpr151 alters the frequency of spontaneous mEPSCs without altering their amplitude, and that it is present on SVs carrying SV2A and other core proteins, it is probable that GPR151 can act directly on the core complex to regulate vesicle release.…”

Brain-to-pancreas signalling axis links nicotine and diabetes

“…However, there are some caveats to consider. TCF7L2 is expressed not only in the mHb, but also in 6 report that activation of these receptors in mice also leads to increases in the release of glucagon and insulin hormones from the pancreas. This leads to increased blood sugar levels -a change associated with an increased risk of diabetes in humans.…”

“…These neurons promote aversive responses to nicotine, but until now, no one knew whether they also control the diabetes-associated effects of smoking -and if so, how. On page 372, Duncan et al 6 identify a signalling pathway that links nAChR-expressing neurons and blood-glucose regulation by the pancreas. It involves a diabetes-associated transcription factor, TCF7L2.…”

“…Disruption of the circadian clock, either because of lifestyle choices or because of mutations in core clock genes, is associated with a higher incidence of tumours 4 . In some tissues, clock genes can be co-opted to promote cancer (they are said to act as oncogenes), whereas in others they act as tumour suppressors [5][6][7] . The origin of such differences is an open question that, when answered, will help researchers to identify the mechanisms by which tumour cells hijack the molecular clock machinery to increase their chances of survival.…”