Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle

The estrogen receptor (ER) designated ER alpha has actions in many cell and tissue types that impact glucose homeostasis. It is unknown if these include mechanisms in endothelial cells, which have the potential to influence relative obesity, and processes in adipose tissue and skeletal muscle that impact glucose control. Here we show that independent of impact on events in adipose tissue, endothelial ER alpha promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle. Endothelial ER alpha-deficient male mice are glucose intolerant and insulin resistant, and in females the antidiabetogenic actions of estradiol (E2) are absent. The glucose dysregulation is due to impaired skeletal muscle glucose disposal that results from attenuated muscle insulin delivery. Endothelial ER alpha activation stimulates insulin transcytosis by skeletal muscle microvascular endothelial cells. Mechanistically this involves nuclear ER alpha-dependent upregulation of vesicular trafficking regulator sorting nexin 5 (SNX5) expression, and PI3 kinase activation that drives plasma membrane recruitment of SNX5. Thus, coupled nuclear and non-nuclear actions of ER alpha promote endothelial insulin transport to skeletal muscle to foster normal glucose homeostasis. Estrogen has anti-diabetic effects via estrogen receptor alpha (ER alpha). Here, authors show that via coupled nuclear and non-nuclear actions, ER alpha in endothelial cells promotes insulin transport to skeletal muscle to foster normal glucose homeostasis.