Evidence for the role of ß2* nAChR desensitization in regulating body weight in obese mice.

ABSTRACT

Nicotine's effect on food intake and body weight has been well documented; however, the relevant receptors underlying these effects have not been firmly established. The purpose of the present study was to (1) identify the nicotinic acetylcholine receptor (nAChR) subtype involved in food intake and body weight; (2) establish whether food intake and body weight reduction produced by nicotinic drugs are due to activation or desensitization of nAChRs; and, (3) assess the role of the melanocortin system in nicotinic drug effects on food intake and body weight. To identify the nAChR, we tested the effect of sazetidine-A (SAZ-A), a relatively selective ligand of ß2-containing nAChRs, on food intake and body weight in obese mice. SAZ-A (3 mg/kg; SC) administered twice-daily significantly decreased food intake and body weight. To assess whether these effects involved desensitization, SAZ-A was administered to non-obese mice via osmotic pump, which, due to its slow sustained drug delivery method, causes prolonged desensitization. SAZ-A via osmotic pump delivery significantly decreased the gain in body weight and reduced food intake. In contrast, body weight was unaffected by SAZ-A in ß2(-/-) mice or in mice lacking the melanocortin 4 receptor (MC4R). These results indicate that ß2 containing nAChRs are essential to SAZ-A's inhibitory effect on body weight and food intake and engage the melanocortin system.