Divergent Roles of α5 and β4 Nicotinic Receptor Subunits in Food Reward and Nicotine-Induced Weight Loss in Male Mice

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Wollesen Breum, Alberte | Falk, Sarah | Svendsen, Charlotte, Sashi Aier | Nicolaisen, Trine Sand | Mathiesen, Cecilie, Vad | Maskos, Uwe | Clemmensen, Christoffer

Edité par CCSD ; Oxford University Press -

International audience. A major obstacle to successful smoking cessation is the prospect of weight gain. Despite a clear relationship between cigarette smoking and body weight, surprisingly little is known about the physiological and molecular mechanism by which nicotine affects energy homeostasis and food motivated behaviors. Here we use loss-of-function mouse models to demonstrate that two nicotinic acetylcholine receptor (nAChR) subunits encoded by the CHRNA5-CHRNA3-CHRNB4 gene cluster, α5 and β4, exhibit divergent roles in food reward. We also reveal that β4-containing nAChRs are essential for the weight-lowering effects of nicotine in diet-induced obese mice. Finally, our data support the notion of cross-talk between incretin biology and nAChR signaling, as we demonstrate that the glycemic benefits of glucagon-like peptide-1 receptor (GLP-1R) activation partially relies on β4-containing nAChRs. Together, these data encourage further research into the role of cholinergic neurotransmission in regulating food reward and the translational pursuit of site-directed targeting of β4-containing nAChRs for treatment of metabolic disease.

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