For today’s topic, cigarette smoking (environmental signal) has an effect on genetic susceptibility (increased risk of type-2 diabetes, i.e. the genome); hence, gene-environment interactions. It has long been known that cigarette smoking increases the risk of type-2 diabetes, because nicotine uptake alters glucose metabolism and increases blood sugar levels. A group of neurons activated by nicotine is located in the brain’s medial habenula (MHb) region; these neurons are characterized by expression of nicotine acetylcholine receptor (nAChR) proteins. These neurons induce an aversion to nicotine (i.e. desire to give up smoking because it is associated with an unpleasant taste); however, until now, it was not known whether these neurons also control diabetes-associated effects of smoking — and if so, how.
Authors [see attached article & editorial] identified a signaling pathway that links nAChR-expressing neurons and blood-glucose regulation by way of the pancreas. The pathway involves a diabetes-associated transcription factor, TCF7L2. TCF7L2 regulates production and secretion of the hormone glucagon-like peptide-1 (GLP1). GLP1 promotes insulin release from the pancreas, and insulin then enhances glucose uptake from the blood into tissues — to be stored as fat; therefore, changes in TCF7L2 expression or activity can influence glucose metabolism. Authors discovered that TCF7L2 is expressed in the medial habenula (MHb). [Hmm, can’t say that I’ve ever heard of ‘the habenula’ before ☹] Given the role of the MHb in the body’s response to nicotine, authors considered the possibility that TCF7L2 expression — in this region of the brain — is involved in nicotine-induced alterations in glucose metabolism.
Authors first generated two transgenic lines of mice: one in which TCF7L2 function was impaired in all tissues, and the other in which the TCF7L2 protein expression could be inhibited specifically in the MHb by introducing a virus carrying a short RNA sequence (siRNA knockdown). Authors then provided the mice with a nicotine solution through a drip — rigged such that the animals could push a lever “to receive an injection of nicotine voluntarily”. Both mouse lines showed greater nicotine intake (i.e. addiction) than did control animals. Prolonged stimulation by nicotine, however, caused nAChR-expressing neurons to become de-sensitized and stop responding to nicotine. Authors determined that TCF7L2 improves the ability of nAChR-expressing neurons to recover from this de-sensitization — thus presumably inducing an aversion to smoking.
Authors [see attached article] identified a multiple-synapse connection from the MHb to the pancreas. Wild-type mice (and rats) —with a history of enjoying nicotine consumption — were shown to increase circulating levels of glucagon and insulin, leading to diabetes-like dysregulation of blood glucose homeostasis. On the contrary, mutant Tcf7l2 rodents (deficient in TCF7L2) were resistant to these actions of nicotine. These data suggest that TCF7L2 regulates the stimulatory actions of nicotine — via the (brain’s) habenula–pancreas axis — that connects the addictive properties of nicotine to its type-2 diabetes-promoting actions. 😊
Nature 17 Oct 2019; 574: 372-377 & News/N/Views editorial pp 336-337