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

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-06-27 DOI:10.1126/science.adj2537

Kyu Sik Kim, Joon Seok Park, Eunsang Hwang, Min Jung Park, Hwa Yun Shin, Young Hee Lee, Kyung Min Kim, Laurent Gautron, Elizabeth Godschall, Bryan Portillo, Kyle Grose, Sang-Ho Jung, So Lin Baek, Young Hyun Yun, Doyeon Lee, Eunseong Kim, Jason Ajwani, Seong Ho Yoo, Ali D. Güler, Kevin W. Williams, Hyung Jin Choi

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引用次数: 0

Abstract

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.

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GLP-1 通过下丘脑回路增加小鼠和人类的餐前饱腹感

GLP-1 受体激动剂（GLP-1RAs）是有效的抗肥胖药物。然而，GLP-1RAs 的确切中枢机制仍然难以捉摸。我们给肥胖症患者服用了 GLP-1RAs 后，观察到他们的餐前饱腹感增强了。对人类和小鼠大脑样本的分析结果表明，背内侧下丘脑（DMH）中的 GLP-1R 神经元是编码进食前饱腹感的候选神经元。对DMH GLP-1R神经元进行光遗传操作可引起饱腹感。钙成像显示，这些神经元积极参与了进食前饱腹感的编码。给予 GLP-1RA 会在进食行为中选择性地增加 DMH GLP-1R 神经元的活性。我们进一步确定了 DMH GLP-1R 神经元与弓状 NPY/AgRP 神经元（ARC NPY/AgRP ）之间错综复杂的相互作用，以调节食物摄入。我们的研究结果揭示了 GLP-1RA 控制进食前饱腹感的下丘脑机制，为肥胖和代谢性疾病提供了新的神经靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

期刊介绍： Science is a leading outlet for scientific news, commentary, and cutting-edge research. Through its print and online incarnations, Science reaches an estimated worldwide readership of more than one million. Science’s authorship is global too, and its articles consistently rank among the world's most cited research. Science serves as a forum for discussion of important issues related to the advancement of science by publishing material on which a consensus has been reached as well as including the presentation of minority or conflicting points of view. Accordingly, all articles published in Science—including editorials, news and comment, and book reviews—are signed and reflect the individual views of the authors and not official points of view adopted by AAAS or the institutions with which the authors are affiliated. Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit recognition by the wider scientific community and general public provided by publication in Science, beyond that provided by specialty journals. Science welcomes submissions from all fields of science and from any source. The editors are committed to the prompt evaluation and publication of submitted papers while upholding high standards that support reproducibility of published research. Science is published weekly; selected papers are published online ahead of print.

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