Glucose-dependent insulinotropic polypeptide receptor signalling in oligodendrocytes increases the weight loss action of GLP1R agonism

Journal article

The next-generation of obesity medicines harness the activity of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors (GIPR, GLP-1R), but their mechanism of action remains to be fully elucidated. Here, we report that the GIPR is enriched in oligodendrocytes of the median eminence (ME) and GIPR signalling bidirectionally regulates oligodendrogenesis in the adult ME of diet-induced obese (DIO) mice. In mice with adult-onset deletion of the GIPR in oligodendrocytes, GIPR agonism fails to enhance the weight-loss and appetite-suppressive effects of GLP-1R agonism. Mechanistically, GIPR agonism increases the access of GLP-1R agonists to the ME and ARH, and GIPR signalling in oligodendrocytes is required for this effect. In addition, we show that vasopressin neurons of the paraventricular hypothalamus, which are necessary for the weight loss induced by GLP1R activation, are targeted by peripherally administered GLP1R agonists via their axonal compartment in the ME. This access is increased by activation of the GIPR in oligodendrocytes in obese mice. Collectively, our findings identify a novel mechanism by which incretin therapies may function to promote synergistic weight loss in the management of excess adiposity.

Authors: Hansford, R; Buller, S; Tsang, AH; Hodson, DJ

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell Metabolism
• Volume: 37
• Issue: 9
• Pages: 1820-1834.e5
• Publication date: 2025-08-13
• Acceptance date: 2025-07-21
• DOI: 10.1016/j.cmet.2025.07.009
• EISSN: 1932-7420
• ISSN: 1550-4131
• Language: English
• Keywords: glucose-dependent insulinotropic peptide; oligodendrocytes; hypothalamus; median eminence; obesity; weight loss; incretin