Adaptive oligodendrogenesis regulates blood-hypothalamus barrier permeability, hypothalamic glucose sensing and systemic glucose homeostasis in male mice
Year: 2026
Type: article
Abstract: OBJECTIVE: Brain glucose sensing is critical for survival during hypoglycaemia, yet how glucose-sensing neurons access circulating glucose concentrations to maintain glucose homeostasis remains poorly understood. Here we tested the hypothesis that adult oligodendrogenesis in the median eminence (ME) is responsive to changes in blood glucose levels and contributes to hypothalamic glucose sensing through regulation of the blood-hypothalamus barrier. METHODS: We used glycemic challenges and hypoinsulinaemic clamp studies to identify the effect of systemic changes in glycaemia on hypothalamic oligodendrocyte lineage cells. We used conditional knockout mouse models to dissect the respective contributions of adult oligodendrogenesis and new myelin formation to glucose homeostasis in adult male mice. Analyses combined immunofluorescence, serial electron microscopy, whole-brain tissue clearing, and transcriptomic analyses. RESULTS: We found that adult oligodendrogenesis in the median eminence (ME) is modulated by changes in circulating glucose levels and rapidly upregulated by hypoglycaemia. Genetic blockade of new oligodendrocyte production in adult male mice impairs the regulation of glucose homeostasis, the integrity of the ME blood-hypothalamus barrier, and hypothalamic glucose sensing. Unexpectedly, functional integrity of adult-formed myelin is not required for the maintenance of glucose homeostasis. Instead, we show that blockade of adult oligodendrogenesis disrupts hypothalamic expression of A disintegrin and metallopeptidase with thrombospondin motifs 4 (ADAMTS4), a metallopeptidase whose brain expression is restricted to the oligodendrocyte lineage and whose ME expression requires ongoing adult oligodendrogenesis. We show that ADAMTS4 regulates hypothalamic perineuronal net deposition, vascular permeability and glucose sensing. Finally, we show that ME ADAMTS4 expression is regulated by changes in peripheral glycaemia and is dysregulated in diabetes, providing a mechanism by which ME oligodendrocytes contribute to the regulation of glucose homeostasis.
Source: Molecular Metabolism
Authors: Sophie Buller, Emily O. Staricoff, Christine Riches, Anthony Tsang, Giada Giavara, Masa Josipovic, Kentaro Ikemura, Gabriel Opoku, Ikumi Sato, Satoshi Hirohata, Saskia Stenzel, Stuart G. Nayar, Marta Ramos Vega, Jacob Hecksher-Sørensen, Sebastian Timmler, Georgina K.C. Dowsett, Brian Y.H. Lam, Giles S.H. Yeo, Kimberly M. Alonge, Huiliang Li, William D. Richardson, Mark L. Evans, Clemence Blouet
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,270
Funders: Leona M. and Harry B. Helmsley Charitable Trust, Wellcome Trust, European Federation of Pharmaceutical Industries and Associations, International Diabetes Federation, Diabetes UK, Innovative Medicines Initiative, Horizon 2020 Framework Programme, Medical Research Council, Japan Society for the Promotion of Science, JDRF
Awards: G2035164500, Anti-atherosclerotic effects of exosomes derived from preconditioned mesenchymal stem cells, Metabolic and Cardiovascular Disease., Decipher cell-cell interactions, Institute of Metabolic Science., Institutional Strategic Support Fund, The University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Cambridge, Adaptive myelination in learning and memory, Characterisation of oligodendrocyte plasticity in the adult median eminence and its role in the regulation of energy balance, Role of median eminence oligodendrocytes in the anti-diabetic action of FGF1, Functional neuromics of the cerebral cortex., G9000192930
OpenAlex ID: W7197004286