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

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 2 nicotinic acetylcholine receptor (nAChR) subunits encoded by the CHRNA5-CHRNA3-CHRNB4 gene cluster, alpha 5 and beta 4, exhibit divergent roles in food reward. We also reveal that beta 4-containing nAChRs are essential for the weight-lowering effects of nicotine in diet-induced obese mice. Finally, our data support the notion of crosstalk between incretin biology and nAChR signaling, as we demonstrate that the glycemic benefits of glucagon-like peptide-1 receptor activation partially relies on beta 4-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 beta 4-containing nAChRs for treatment of metabolic disease.

Automated summary

The physiological and molecular mechanisms by which nicotine affects energy homeostasis and food-motivated behaviors are not well understood. This study demonstrates the divergent roles of alpha 5 and beta 4 subunits of nicotinic acetylcholine receptors (nAChRs) in food reward and the essential role of beta 4-containing nAChRs in the weight-lowering effects of nicotine in obese mice. The study also suggests a crosstalk between incretin biology and nAChR signaling through beta 4-containing nAChRs. Further research into cholinergic neurotransmission and targeted treatments involving beta 4-containing nAChRs is encouraged.