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 DMH GLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMH GLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMH GLP-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.

中文翻译：

---

GLP-1 通过下丘脑回路增加小鼠和人类的摄入前饱腹感


胰高血糖素样肽-1 (GLP-1) 受体激动剂 (GLP-1RA) 是有效的抗肥胖药物。然而，GLP-1RA 的精确中心机制仍然难以捉摸。我们给肥胖患者服用 GLP-1RA，并观察到摄入前饱腹感增强。对人类和小鼠大脑样本的分析确定了下丘脑背内侧 (DMH) 中的 GLP-1 受体 (GLP-1R) 神经元是编码摄入前饱足感的候选神经元。 DMH 的光遗传学操作GLP-1R神经元引起饱足感。钙成像表明这些神经元积极参与编码摄入前饱足感。 GLP-1RA 给药增加 DMH 活性GLP-1R神经元在进食行为期间选择性地。我们进一步发现 DMH 之间错综复杂的相互作用GLP-1R弓状核神经元和神经肽 Y/agouti 相关肽神经元 (ARC NPY/AgRP神经元）的作用是调节食物摄入量。我们的研究结果揭示了 GLP-1RA 控制摄入前饱足感的下丘脑机制，为肥胖和代谢疾病提供了以前未探索过的神经靶标。