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Glucose-sensing neurons in the brainstem participate in the regulation of energy homeostasis but have been poorly characterized because of the lack of specific markers to identify them. Here we show that GLUT2-expressing neurons of the nucleus of the tractus solitarius form a distinct population of hypoglycemia-activated neurons. Their response to low glucose is mediated by reduced intracellular glucose metabolism, increased AMP-activated protein kinase activity, and closure of leak K+ channels. These are GABAergic neurons that send projections to the vagal motor nucleus. Light-induced stimulation of channelrhodospin-expressing GLUT2 neurons in vivo led to increased parasympathetic nerve firing and glucagon secretion. Thus GLUT2 neurons of the nucleus tractus solitarius link hypoglycemia detection to counterregulatory response. These results may help identify the cause of hypoglycemia-associated autonomic failure, a major threat in the insulin treatment of diabetes.

Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity 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 CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation. Serotonin turnover and expression of 5HT2A and 5HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that 5HT2A, but surprisingly not 5HT2C, receptor is critical for weight-loss, anorexia and fat mass reduction induced by central GLP-1R activation. Importantly, central 5HT2A 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 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 new critical neural substrate for GLP-1 impact on energy homeostasis, and expands the current map of brain areas impacted by GLP-1R activation.