Abstract
A recent report suggested that brain-derived serotonin (5-HT) is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1) receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph) inhibitor p-chlorophenylalanine (PCPA) for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high-affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors.
Highlights
Central serotonin (5-HT) systems have a critical role in the regulation of appetite and body weight
In the present study, to determine whether 5HT is critical for the weight loss induced by glucagon-like peptide1 (GLP-1) receptor activation in mice, we examined the effects of liraglutide on daily food intake and body weight over 4 days in mice treated with or without the tryptophan hydroxylase inhibitor pchlorophenylalanine (PCPA) for 3 days
To evaluate the relationship between the acute anorexic effects of the GLP-1 receptor agonist and the expression of hypothalamic 5-HT2A receptors, we examined the effect of liraglutide on the expression of hypothalamic 5-HT2A and 5-HT2C receptors in mice, which are responsive to the administration of liraglutide
Summary
Central serotonin (5-HT) systems have a critical role in the regulation of appetite and body weight. Central serotonin 5-HT2C receptors contribute to the leptin-independent regulation of appetite [1]. We previously reported that the acute anorexic effects of liraglutide in mice do not require central 5-HT and functional leptin receptor signaling [2]. A recent report by Anderberg et al, suggested that brain-derived 5-HT is critical for maintaining weight loss induced by GLP-1 receptor activation and pharmacologic blockade of central serotonin 5-HT2A receptors using R-. In the present study, to determine whether 5HT is critical for the weight loss induced by GLP-1 receptor activation in mice, we examined the effects of liraglutide on daily food intake and body weight over 4 days in mice treated with or without the tryptophan hydroxylase inhibitor pchlorophenylalanine (PCPA) for 3 days.
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