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<p>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.</p>

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Endothelial IRE1α promotes thrombospondin-1 mRNA decay and supports metabolic stress adaptation of pancreatic islets

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Xiaoge Zhang,
  • Shijia Huang,
  • Peng Chen,
  • Ziyin Zhang,
  • Jie Cai,
  • Ting Yu,
  • Zhixiong Xia,
  • Shubo Yuan,
  • Yong Chen,
  • Mengjuan Gao,
  • Zhuyin Wu,
  • Jiongyi He,
  • Yifei Liao,
  • Qi Fu,
  • Qiong Yang,
  • Tailang Yin,
  • Jie Liu,
  • Ke Song,
  • Sheng-Zhong Duan,
  • Tao Yang,
  • Liangyou Rui,
  • Yi Arial Zeng,
  • Zhuo-Xian Meng,
  • Jianmiao Liu,
  • Yong Liu

摘要

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.