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

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Jun 10, 2024 version files 372.73 MB
Jul 16, 2024 version files 372.64 MB

Abstract

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.