2025-06-13 カロリンスカ研究所(KI)
<関連情報>
- https://news.ki.se/western-diet-can-cause-permanent-pancreatic-damage-new-study-finds
- https://www.jci.org/articles/view/177601
食事誘発性肥満はVEGF-Aに対する内皮細胞の脱感作を促進し、マウス膵島血管の永久的機能不全を引き起こす Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice
Yan Xiong, Andrea Dicker, Montse Visa, Erwin Ilegems, and Per-Olof Berggren
The Journal of Clinical Investigation Published: June 9, 2025
DOI:https://doi.org/10.1172/JCI177601
Graphical abstract
Abstract
Pancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis in obesity and its role in the manifestation of metabolic disorders remain understudied. Here, we depict the time-resolved decline of intra-islet endothelial cell responsiveness to vascular endothelial cell growth factor A (VEGF-A) and islet vessel function in a mouse model of diet-induced obesity. Longitudinal imaging of sentinel islets transplanted into mouse eyes revealed substantial vascular remodeling and diminished VEGF-A response in islet endothelial cells after 12 weeks of western diet (WD) feeding. This led to islet vessel barrier dysfunction and hemodynamic dysregulation, delaying transportation of secreted insulin into the blood. Notably, islet vessels exhibited a metabolic memory of previous WD feeding. Neither VEGF-A sensitivity nor the other vascular alterations was fully restored by control diet (CD) refeeding, resulting in modest yet significant impairment in glucose clearance despite normalized insulin sensitivity. Mechanistic analysis implicated hyperactivation of atypical protein kinase C (aPKC) under both WD and recovery conditions, which inhibited VEGF receptor 2 (VEGFR2) internalization and blunted VEGF-A triggered signal transduction in endothelial cells. In summary, prolonged WD feeding causes irreversible islet endothelial cell desensitization to VEGF-A and islet vessel dysfunction, directly undermining glucose homeostasis.
