英国艾登布鲁克医院Clemence Blouet团队的研究显示，少突胶质细胞中葡萄糖依赖的嗜胰岛素多肽受体信号增加GLP-1R激动作用的减肥作用。这一研究成果发表在2025年8月13日出版的国际学术期刊《细胞—代谢》上。

该课题组报道了GIPR在少突胶质细胞中富集，并且GIPR信号双向调节少突胶质细胞的发生。在少突胶质细胞中GIPR缺失的小鼠中，GIPR激动作用不能增强GLP-1R激动作用的减肥效果。从机制上讲，GIPR激动作用增加了GLP-1R激动剂的脑通路，而这种作用需要少突胶质细胞中的GIPR信号传导。此外，该研究组发现室旁下丘脑的抗利尿激素神经元对于GLP-1R激活的减肥反应是必要的，通过外周给药GLP-1R激动剂通过其轴突室靶向，这种通路通过激活少突胶质细胞中的GIPR而增加。总的来说，他们的发现确定了一种新的机制，通过这种机制，肠促胰岛素疗法可能在过度肥胖的管理中促进协同减肥。

研究人员表示，下一代肥胖药物利用葡萄糖依赖性胰岛素性多肽和胰高血糖素样肽1受体（GIPR和GLP-1R）的活性，但其作用机制尚不清楚。

附：英文原文

Title: Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism

Author: Robert Hansford, Sophie Buller, Anthony H. Tsang, Simon Benoit, Anna G. Roberts, Emmy Erskine, Thomas Brown, Valentina Pirro, Frank Reimann, Norio Harada, Nobuya Inagaki, Ricardo J. Samms, Johannes Broichhagen, David J. Hodson, Alice Adriaenssens, Soyoung Park, Clemence Blouet

Issue&Volume: 2025-08-13

Abstract: The next generation of obesity medicines harness the activity of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors (GIPR and GLP-1R), but their mechanism of action remains unclear. Here, we report that the GIPR is enriched in oligodendrocytes and GIPR signaling bidirectionally regulates oligodendrogenesis. In mice with adult-onset deletion of GIPR in oligodendrocytes, GIPR agonism fails to enhance the weight-loss effects of GLP-1R agonism. Mechanistically, GIPR agonism increases brain access of GLP-1R agonists, and GIPR signaling in oligodendrocytes is required for this effect. In addition, we show that vasopressin neurons of the paraventricular hypothalamus are necessary for the weight-loss response to GLP-1R activation, targeted by peripherally administered GLP-1R agonists via their axonal compartment, and this access is increased by activation of the GIPR in oligodendrocytes. Collectively, our findings identify a novel mechanism by which incretin therapies may function to promote synergistic weight loss in the management of excess adiposity.

DOI: 10.1016/j.cmet.2025.07.009

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00355-9