Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight

Jan 7, 2017Diabetes

Glucagon-Like Peptide 1 and Similar Drugs Affect the Brain's Serotonin System to Lower Appetite and Body Weight

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Abstract

Serotonin depletion impaired the ability of exendin-4 to reduce body weight in rats.

GLP-1 and serotonin are both involved in regulating energy balance.
Activation of GLP-1 receptors alters serotonin turnover and receptor expression in the hypothalamus.
The 5-HT receptor, but not the 5-HT receptor, is necessary for weight loss and reduced fat mass associated with GLP-1 receptor activation.
Serotonin is required for the weight-reducing effects of liraglutide, a GLP-1 analog, when administered peripherally.
Stimulation of GLP-1 receptors in the dorsal raphe increases the activity of serotonin-producing neurons and reduces food intake.

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Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT) and 5-HTserotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT, but surprisingly not the 5-HT, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HTreceptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation. 2A2C2A2C2A

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Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight

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