Abstract
Vascular endothelial cells (ECs) play pivotal roles in maintaining metabolic tissue homeostasis, and EC dysfunction is associated with obesity and metabolic disorders. The mammalian ER stress sensor IRE1α kinase/RNase responds to metabolic cues, but it remains unclear whether endothelial IRE1α is implicated in controlling systemic metabolism. Here we show that genetic depletion of IRE1α in ECs leads to maladaptation of pancreatic islets under obesity-associated metabolic stress. We find that in high-fat diet-fed male mice, loss of IRE1α in ECs has no significant impact upon adiposity, but unexpectedly results in glucose intolerance with impaired insulin secretion, accompanied by blunted intra-islet angiogenesis and compensatory islet growth. Mechanistically, IRE1α RNase decays the mRNA encoding the endogenous anti-angiogenic factor thrombospondin-1 (THBS1/TSP1) in islet ECs. These findings thus uncover a critical role of the endothelial IRE1α suppression of THBS1 in governing the vascular support that enables the functional adaptation of islets to metabolic stress.
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Data availability
The raw RNA-seq data generated in this study have been deposited in the GEO database under the accession code GSE263586. In addition, we also analyzed previously published single-cell RNA-seq data GSE203376 from primary pancreatic islets in normal chow- versus HFD-fed mice. Source data are provided with this paper.
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Acknowledgements
We thank Qian Liu and Mingliang Tang for assistance at the animal and microscopy core facilities. This work was supported by grants from the National Natural Science Foundation of China (82230026, 32021003, 92357307, 91857204) and from the Ministry of Science and Technology of China (National Key R&D Program of China 2024YFA1802800 and 2018YFA0800700) to Y Liu, as well as from the National Natural Science Foundation of China (32501063) and the Postdoctoral Fellowship Program of CPSF (GZC20251881) to X.Z. Also supported by Shenzhen Medical Research Fund (B2402004) to Jie Liu and Y Liu.
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X.Z., J.L. and Y.Liu. conceived and designed the studies. X.Z., S.H. and P.C. performed most of the experiments and analyzed the data. Z.Z., J.C., Ting.Y., Z.X., Y.C., M.G., Z.W., J.H., Y.Liao. and S.Y. conducted the cell or animal experiments. Q.F. and T.Y. assisted with scRNA-seq data. Q.Y., Tailang Y., K.S., Jie L, S.D., L.R., Y.A.Z., and Z.M. provided essential technical support and assisted with HUVEC isolation and islet analysis. X.Z., S.H., J.L. and Y.Liu wrote and edited the manuscript.
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Zhang, X., Huang, S., Chen, P. et al. Endothelial IRE1α promotes thrombospondin-1 mRNA decay and supports metabolic stress adaptation of pancreatic islets. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68276-1
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DOI: https://doi.org/10.1038/s41467-025-68276-1
