α4β2 nicotinic acetylcholine receptors intrinsically influence body weight in mice.

Desensitization of the nicotinic acetylcholine receptor (nAChR) containing the β2 subunit is a potentially critical mechanism underlying the body weight (BW) reducing effects of nicotine. The purpose of this study was a) to determine the α subunit(s) that partners with the β2 subunit to form the nAChR subtype that endogenously regulates energy balance and b) to probe the extent to which nAChR desensitization could be involved in the regulation of BW. We demonstrate that deletion of either the α4 or the β2, but not the α5, subunit of the nAChR suppresses weight gain in a sex-dependent manner. Furthermore, chronic treatment with the β2-selective nAChR competitive antagonist dihydro-β-erythroidine (DHβE) in mice fed a high-fat diet suppresses weight gain. These results indicate that heteromeric α4β2 nAChRs play a role as intrinsic regulators of energy balance and that desensitizing or inhibiting this nAChR is likely a relevant mechanism and thus could be a strategy for weight loss.