GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans

• 成果类型: Article
• 署名作者: Kim, Kyu Sik; Park, Joon Seok; Hwang, Eunsang; Park, Min Jung; Shin, Hwa Yun; Lee, Young Hee; Kim, Kyung Min; Gautron, Laurent; Godschall, Elizabeth; Portillo, Bryan; Grose, Kyle; Jung, Sang-Ho; Baek, So Lin; Yun, Young Hyun; Lee, Doyeon; Kim, Eunseong; Ajwani, Jason; Yoo, Seong Ho; Gueler, Ali D.; Williams, Kevin W.; Choi, Hyung Jin
• 署名单位: Seoul National University (SNU); University of Texas System; University of Texas Southwestern Medical Center; Seoul National University (SNU); University of Virginia; Seoul National University (SNU); University of London; University College London; Seoul National University (SNU); Seoul National University (SNU); Seoul National University (SNU); Seoul National University (SNU)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11811
• DOI: 10.1126/science.adj2537
• 发表日期: 2024-07-26
• 页码: 438-446
• 关键词: glucagon-like peptide-1; receptor-expressing cells; appetite; BEHAVIOR; nucleus; modulation; neurons

摘要

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