Park Joon Seok, Kim Kyu Sik, Choi Hyung Jin
Department of Medicine, Seoul National University College of Medicine, Seoul, Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Diabetes Metab J. 2025 May;49(3):333-347. doi: 10.4093/dmj.2025.0106. Epub 2025 May 1.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)-a key GLP-1RA target-mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.
胰高血糖素样肽-1受体激动剂（GLP-1RAs）已成为治疗代谢性疾病的重磅药物。胰高血糖素样肽-1（GLP-1）通过增强胰岛素分泌、抑制胰高血糖素释放、延缓胃排空以及作用于中枢神经系统来调节饱腹感，在葡萄糖稳态中发挥关键作用。本综述总结了GLP-1的发现及GLP-1RAs的研发，尤其关注它们的中枢作用机制。人体神经影像学研究表明，GLP-1RAs在食物认知过程中会影响大脑活动，支持其在进食前饱腹感方面的作用。关于下丘脑对饥饿的前馈调节的动物研究表明，认知性下丘脑机制也可能有助于饱腹感控制。我们重点介绍了GLP-1RA诱导饱腹感和饱足感的脑机制，包括认知影响，特别强调了对下丘脑胰高血糖素样肽-1受体（GLP-1R）和表达GLP-1R的神经元的动物研究。还讨论了其在非下丘脑区域的作用。此外，我们综述了旨在提高疗效和患者依从性的新型联合药物及口服GLP-1RA制剂。总之，下丘脑背内侧核（DMH）——GLP-1RA的关键靶点——介导进食前的认知性饱腹感，而下丘脑其他表达GLP-1R的神经元则调节进食行为的多个方面，为肥胖治疗提供了潜在的治疗靶点。
