Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression.
This preclinical study investigated the neurological mechanisms by which obesity medications suppress food intake, focusing on proglucagon (PPG)-expressing neurons in the nucleus of the solitary tract (PPG-NTS). Using single-nucleus RNA sequencing and histochemistry, researchers characterized gene expression profiles of PPG-NTS neurons in rodents, finding that serotonin 2C receptors (5-HT2CR) — the target of lorcaserin — were widely expressed in these neurons, while GLP-1 receptors and melanocortin-4 receptors were not. Lorcaserin was found to significantly activate PPG-NTS neurons. When PPG-NTS neurons were virally ablated, lorcaserin lost its ability to suppress food intake, whereas the MC4R agonist melanotan-II retained its effect, confirming the functional role of 5-HT2CR expression in these neurons. Additionally, combining lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction than either drug alone. The study concludes that PPG-NTS neurons are a necessary mechanistic link for lorcaserin's appetite-suppressing effects and suggests that combining 5-HT2CR and GLP-1R agonists may enhance therapeutic outcomes. Key limitations include that all experiments were conducted in animals, and translational relevance to humans remains to be established.