GLP-1 Increases pre-ingestive satiation via hypothalamic circuits in mice and humans

GLP-1 receptor agonists (GLP-1RAs) are effective anti-obesity drugs.
However, the precise central mechanisms of GLP-1RAs remain elusive. We
administered GLP-1RAs to obese patients and observed heightened sense of
pre-ingestive satiation. Analysis of human and mouse brain samples
pinpointed GLP-1R neurons in the dorsomedial hypothalamus (DMH) as
candidates for encoding pre-ingestive satiation. Optogenetic manipulation
of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that
these neurons are actively involved in encoding pre-ingestive satiation.
GLP-1RA administration increased the activity of DMHGLP-1R neurons
selectively during eating behavior. We further identified an intricate
interplay between DMHGLP-1R neurons and arcuate NPY/AgRP neurons
(ARCNPY/AgRP), to regulate food intake. Our findings reveal a hypothalamic
mechanism through which GLP-1RAs control pre-ingestive satiation, offering
novel neural targets for obesity and metabolic diseases.