How GLP-1 receptor agonists mediate the feeling of fullness in mice and humans

GLP-1 receptor agonists promote the feeling of fullness before eating via neurons in the dorsomedial hypothalamus, according to a new study. The findings offer new insights into the neural pathways by which GLP-1 receptor agonists increase the feeling of fullness to prevent overconsumption of food, which is key in mitigating obesity. Glucagon-like-peptide-1 (GLP-1) plays an important role in signaling the feeling of fullness after eating. Preingestive satiation is a phenomenon that occurs before actual food intake, allowing animals to regulate internal status and prepare for changes. Recently, GLP-1 receptor agonists (GLP-1RAs) have proven effective in treating obesity by affecting food cognition, diminishing hypothalamic responses to food cues, and altering food palatability perception. These findings suggest that GLP-1RAs may play a role in preingestive satiation to control food intake. However, the central mechanisms underlying these effects are poorly understood, and the targets of GLP-1RAs remain controversial. Here, Kyu Sik Kim and colleagues present the results of a phase-specific clinical trial involving obese individuals. Kim et al. conducted satiation surveys at baseline, pre-ingestive, and ingestive phases, with or without GLP-1RA treatment. The results showed that GLP-1RA treatment consistently increased the satiation index (overall feeling of fullness) across all phases, while the control group showed a decline from baseline to pre-ingestive phase. In the pre-ingestive phase, GLP-1RA significantly increased the satiation index compared to baseline, enhancing prospective food ingestion, food reward, and motivation satiation indices. Through analysis of human and mouse brain samples, Kim et al. identified neural circuits in the dorsomedial hypothalamus that interact with these agonists to induce dampening of the desire for food. Optogenetic manipulation of these neurons caused satiation and calcium imaging demonstrated their active involvement in encoding preingestive satiation.