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

Anastasia Sacharidou, Ken Chambliss, Jun Peng, Jose Barrera, Keiji Tanigaki, Katherine Luby-Phelps, İpek Özdemir, Sohaib Khan, Shashank R. Sirsi, Sung Hoon Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Mohammed Kanchwala, Adwait A. Sathe, Andrew Lemoff, Chao Xing, Kenneth Hoyt, Chieko Mineo () and Philip W. Shaul ()
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Anastasia Sacharidou: University of Texas Southwestern Medical Center
Ken Chambliss: University of Texas Southwestern Medical Center
Jun Peng: University of Texas Southwestern Medical Center
Jose Barrera: University of Texas Southwestern Medical Center
Keiji Tanigaki: University of Texas Southwestern Medical Center
Katherine Luby-Phelps: University of Texas Southwestern Medical Center
İpek Özdemir: University of Texas at Dallas
Sohaib Khan: University of Cincinnati College of Medicine
Shashank R. Sirsi: University of Texas at Dallas
Sung Hoon Kim: University of Illinois at Urbana-Champaign
Benita S. Katzenellenbogen: University of Illinois at Urbana-Champaign
John A. Katzenellenbogen: University of Illinois at Urbana-Champaign
Mohammed Kanchwala: University of Texas Southwestern Medical Center
Adwait A. Sathe: University of Texas Southwestern Medical Center
Andrew Lemoff: University of Texas Southwestern Medical Center
Chao Xing: University of Texas Southwestern Medical Center
Kenneth Hoyt: University of Texas at Dallas
Chieko Mineo: University of Texas Southwestern Medical Center
Philip W. Shaul: University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The estrogen receptor (ER) designated ERα 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 ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle. Endothelial ERα-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 ERα activation stimulates insulin transcytosis by skeletal muscle microvascular endothelial cells. Mechanistically this involves nuclear ERα-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 ERα promote endothelial insulin transport to skeletal muscle to foster normal glucose homeostasis.

Date: 2023
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DOI: 10.1038/s41467-023-40562-w

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