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-HT1B, 5-HT2C and 5-HT6 receptors and these are therefore receiving increasing attention as principal pharmacotherapeutic targets for the treatment of obesity. The 5-HT2C 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-HT2C receptor RNA is fully edited, suggesting a potential role for 5-HT2C 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-HT2C receptor editing. Using a leptin-deficient mouse model of obesity (ob/ob), we show increased hypothalamic 5-HT1A receptor expression as well as increased hippocampal 5-HT1A, 5-HT1B, and 5-HT6 receptor mRNA expression in obese mice compared to lean control mice. An increase in full-length 5-HT2C expression, depending on time of day, as well as differences in 5-HT2C receptor editing were found, independent of changes in total 5-HT2C receptor mRNA expression. This suggests that a dynamic regulation exists of the appetite-suppressing effects of the 5-HT2C receptor in both the hypothalamus and the hippocampus in the ob/ob mice model of obesity. The differential 5-HT1A, 5-HT1B and 5-HT6 receptor expression and altered 5-HT2C receptor editing profile reported here is poised to have important consequences for the development of novel anti-obesity therapies.
Highlights
Obesity is rapidly increasing in prevalence in developed countries [1,2]
This study demonstrates significant increases in hypothalamic 5-HT1A and 5-HT2C receptor mRNA expression as well as in hippocampal 5-HT1A, 5-HT1B and 5-HT6 receptor expression in obese mice compared to lean control
We suggest that 5-HT2C receptor mRNA expression changes and 5-HT2C receptor editing may play a key role in the observed hyperphagic phenotype in the leptin-deficient obese mouse model
Summary
Obesity is rapidly increasing in prevalence in developed countries [1,2]. There is increasing medical and societal needs for novel treatments, which induce appetite suppression and weight loss. Acting serotonergic agents, including sibutramine, m-chlorophenylpiperazine (mCPP) and fenfluramine, act as potent appetite suppressants [16,17,18]. These compounds are pharmacologically promiscuous, showing activity across multiple 5-HT and non-5-HT pathways and receptors, and exert many unwanted side effects. A better understanding of the mechanisms by which serotonergic receptors regulate appetite and energy homeostasis may lead to the development of novel effective anti-obesity drugs
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