OBJECTIVE: Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HTR; e.g, lorcaserin), and melanocortin4 (MC4R) which reduce body weight primarily by suppressing food intake. However, the mechanisms underlying the therapeutic food intake suppressive effects are still being defined and were investigated here. 2C
METHODS: We profiled PPG neurons in the nucleus of the solitary tract (PPG) using single nucleus RNA sequencing (Nuc-Seq) and histochemistry. We next examined the requirement of PPGneurons for obesity medication effects on food intake by virally ablating PPGneurons. Finally, we assessed the effects on food intake of the combination of liraglutide and lorcaserin. NTS NTS NTS
RESULTS: We found that 5-HTRs, but not GLP-1Rs or MC4Rs, were widespread in PPGclusters and that lorcaserin significantly activated PPGneurons. Accordingly, ablation of PPGneurons prevented the reduction of food intake by lorcaserin but not MC4R agonist melanotan-II, demonstrating the functional significance of PPG5-HTR expression. Finally, the combination of lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction as compared to either monotherapy. 2C2C NTS NTS NTS NTS
CONCLUSIONS: These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPGneurons. Moreover, these data reveal a strategy to augment the therapeutic profile of the current frontline treatment for obesity, GLP-1R agonists, via coadministration with 5-HTR agonists. NTS2C
