title: Evidence for the role of β2* 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 β2-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 β2(-/-) mice or in mice lacking the melanocortin 4 receptor (MC4R). These results indicate that β2 containing nAChRs are essential to SAZ-A's inhibitory effect on body weight and food intake and engage the melanocortin system.
authors.affiliation: Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, D.C., USA.
authors.forename: Ghazaul
authors.initials: G
authors.lastname: Dezfuli
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, D.C., USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kellar
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, D.C., USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Dretchen
authors.affiliation: Department of Pharmacology, College of Medicine, Howard University, Washington, D.C., USA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Tizabi
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, D.C., USA. Electronic address: sahibzan@georgetown.edu.
authors.forename: Niaz
authors.initials: N
authors.lastname: Sahibzada
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, D.C., USA. Electronic address: gillisr@georgetown.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gillis
mesh_terms: D000818:Animals; D001384:Azetidines / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D007260:Infusion Pumps; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009538:Nicotine / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D011978:Receptors, Nicotinic / Q000502:physiology*
chemical_list: D001384:Azetidines; D009538:Nicotine; D011725:Pyridines; D011978:Receptors, Nicotinic; C514816:sazetidine-A
keywords: Body weight; Food intake; Melanocortin; Nicotine; Sazetidine-A