Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin

Hua Mao, Luge Li, Qiying Fan, Aude Angelini, Pradip K. Saha, Cristian Coarfa, Kimal Rajapakshe, Dimuthu Perera, Jizhong Cheng, Huaizhu Wu, Christie M. Ballantyne, Zheng Sun, Liang Xie and Xinchun Pi ()
Additional contact information
Hua Mao: Section of Athero & Lipo, Baylor College of Medicine
Luge Li: Section of Athero & Lipo, Baylor College of Medicine
Qiying Fan: Section of Athero & Lipo, Baylor College of Medicine
Aude Angelini: Section of Athero & Lipo, Baylor College of Medicine
Pradip K. Saha: Baylor College of Medicine
Cristian Coarfa: Baylor College of Medicine
Kimal Rajapakshe: Baylor College of Medicine
Dimuthu Perera: Baylor College of Medicine
Jizhong Cheng: Baylor College of Medicine
Huaizhu Wu: Section of Athero & Lipo, Baylor College of Medicine
Christie M. Ballantyne: Section of Athero & Lipo, Baylor College of Medicine
Zheng Sun: Baylor College of Medicine
Liang Xie: Section of Athero & Lipo, Baylor College of Medicine
Xinchun Pi: Section of Athero & Lipo, Baylor College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.

Date: 2021
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DOI: 10.1038/s41467-021-25673-6

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