Vascular endothelial IRE1α 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 IRE1α selectively impaired the compensatory adaptation of pancreatic islet function in response to metabolic stress. Loss of IRE1α 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, IRE1α 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 IRE1α deficiency in ECs. Together, our findings demonstrate a critical role of the endothelial IRE1α suppression of THBS1 in governing the vascular support that enables the homeostatic adaptation of pancreatic islets to cope with overnutrition-associated metabolic stress.