Endothelium-Specific Depletion of LRP1 Improves Glucose Homeostasis Through Inducing Osteocalcin

Authors

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
Xinchun Pi

Publication Date

9-6-2021

Journal

Nature Communications

DOI

10.1038/s41467-021-25673-6

PMID

34489478

PMCID

PMC8421392

PubMedCentral® Posted Date

9-6-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Endothelial Cells, Endothelium, Vascular, Forkhead Box Protein O1, Gene Expression Regulation, Genes, Reporter, Glucose, Glucose Tolerance Test, Green Fluorescent Proteins, HEK293 Cells, Humans, Hyperglycemia, Insulin, Insulin Receptor Substrate Proteins, Insulin-Secreting Cells, Low Density Lipoprotein Receptor-Related Protein-1, Male, Mice, Mice, Knockout, Osteoblasts, Osteocalcin, Proto-Oncogene Proteins c-akt, Receptor, IGF Type 1, Receptors, G-Protein-Coupled, Signal Transduction, Checkpoint signalling, Type 1 diabetes, Type 2 diabetes

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.

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