To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake. The brain serotonin pathway regulates appetite and body weight. D'Agostino, Heisler et al. show that the anti-obesity 5-HT2CR agonist lorcaserin targets both the POMC circuitry of the hypothalamus and the brainstem nucleus of the solitary tract (5-HT2CRNTS) to mediate appetite suppression.
D’Agostino, G., Lyons, D., Cristiano, C., Lettieri, M., Olarte-Sanchez, C., Burke, L. K., … Heisler, L. K. (2018). Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake. Cell Metabolism, 28(4), 619-630.e5. https://doi.org/10.1016/j.cmet.2018.07.017