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

• 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-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Aminopyridines/pharmacology

Animals

Anorexia

Appetite/*drug effects

Body Weight/*drug effects

Dorsal Raphe Nucleus/*metabolism

Feeding Behavior/drug effects

Fenclonine/pharmacology

Glucagon-Like Peptide 1/*pharmacology

Glucagon-Like Peptide-1 Receptor/*drug effects/metabolism

Hypoglycemic Agents/*pharmacology

Indoles/pharmacology

Liraglutide/pharmacology

Male

Peptides/pharmacology

Pyrrolidines/pharmacology

Rats

Rats

Sprague-Dawley

Receptor

Serotonin

5-HT2A/*drug effects/metabolism

Receptor

Serotonin

5-HT2C/*drug effects/metabolism

Serotonin/*metabolism

Serotonin Antagonists/pharmacology

Venoms/pharmacology

Weight Loss/drug effects

Publikations- och innehållstyp

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