Vascular endothelial IRE1a promotes thrombospondin-1 mRNA decay and supports the functional adaptation of pancreatic islets upon metabolic stress

It remains unknown whether ER stress response signaling has a metabolic regulatory role in ECs. Here, in mice with high-fat diet-induced obesity, we found that EC-specific ablation of IRE1a selectively impaired the compensatory adaptation of pancreatic islet function in response to metabolic stress. Loss of IRE1a in ECs resulted in significantly lower intra-islet angiogenesis, accompanied by defects in the compensatory growth of pancreatic islets and their capacity of glucose-stimulated insulin secretion, consequently leading to hyperglycemia. Mechanistically, IRE1a could downregulate the intra-islet EC expression of the mRNA encoding thrombospondin-1 (THBS1/TSP1), an endogenous anti-angiogenic factor implicated in islet function regulation and prediabetes, through its RIDD activity. Importantly, EC-specific depletion of THBS1 completely corrected these islet dysfunctions arising from IRE1a deficiency in ECs. Together, our findings demonstrate a critical role of the endothelial IRE1a suppression of THBS1 in governing the vascular support that enables the homeostatic adaptation of pancreatic islets to cope with overnutrition-associated metabolic stress. Overall design: To investigate the physiological functions of IRE1a in endothelial cells under the challenge of excess nutrition, we generated endothelial cell IRE1a deletion strain and established a high fat diet (HFD)-induced obesity model. We intercrossed floxed IRE1a (Ern1fl/fl) mice with the VE-cadherin-CreERT2 line to create vascular endothelial cell-specific IRE1a-knockout (Ern1EC-KO) mice by a tamoxifen (Tam)-inducible system.To explore how IRE1a promotes intra-islets angiogenesis, we performed bulk RNA-seq transcriptome analysis of islets from Ern1fl/fl and Ern1EC-KO mice after 16-weeks HFD feeding.