title: Dynamic 5-HT2C receptor editing in a mouse model of obesity.
abstract: The central serotonergic signalling system has been shown to play an important role in appetite control and the regulation of food intake. Serotonin exerts its anorectic effects mainly through the 5-HT(1B), 5-HT(2C) and 5-HT(6) receptors and these are therefore receiving increasing attention as principal pharmacotherapeutic targets for the treatment of obesity. The 5-HT(2C) receptor has the distinctive ability to be modified by posttranscriptional RNA editing on 5 nucleotide positions (A, B, C, D, E), having an overall decreased receptor function. Recently, it has been shown that feeding behaviour and fat mass are altered when the 5-HT(2C) receptor RNA is fully edited, suggesting a potential role for 5-HT(2C) editing in obesity. The present studies investigate the expression of serotonin receptors involved in central regulation of food intake, appetite and energy expenditure, with particular focus on the level of 5-HT(2C) receptor editing. Using a leptin-deficient mouse model of obesity (ob/ob), we show increased hypothalamic 5-HT(1A) receptor expression as well as increased hippocampal 5-HT(1A), 5-HT(1B), and 5-HT(6) receptor mRNA expression in obese mice compared to lean control mice. An increase in full-length 5-HT(2C) expression, depending on time of day, as well as differences in 5-HT(2C) receptor editing were found, independent of changes in total 5-HT(2C) receptor mRNA expression. This suggests that a dynamic regulation exists of the appetite-suppressing effects of the 5-HT(2C) receptor in both the hypothalamus and the hippocampus in the ob/ob mice model of obesity. The differential 5-HT(1A), 5-HT(1B) and 5-HT(6) receptor expression and altered 5-HT(2C) receptor editing profile reported here is poised to have important consequences for the development of novel anti-obesity therapies.
authors.affiliation: Food for Health Ireland, University College Cork, Cork, Ireland.
authors.forename: Harriët
authors.initials: H
authors.lastname: Schellekens
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.forename: Ian B
authors.initials: IB
authors.lastname: Jeffery
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D001066:Appetite / Q000235:genetics; D001069:Appetite Regulation / Q000235:genetics; D004195:Disease Models, Animal; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism; D005247:Feeding Behavior; D020738:Leptin / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics*; D017393:RNA Editing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D011985:Receptors, Serotonin / Q000235:genetics; D012701:Serotonin / Q000378:metabolism; D013851:Thinness / Q000235:genetics*
chemical_list: D020738:Leptin; D012333:RNA, Messenger; D044302:Receptor, Serotonin, 5-HT1B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; D012701:Serotonin; D000243:Adenosine Deaminase