Journal Article

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

Hua Mao, Huaizhu Wu, Liang Xie, Christie M. Ballantyne, Xinchun Pi, Luge Li, Cristian Coarfa, Qiying Fan, Kimal Rajapakshe, Pradip K. Saha, Jizhong Cheng, Zheng Sun, Dimuthu Perera, Aude Angelini

2021

Overview

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. The vascular endothelium contributes to metabolic regulation, however, the underlying mechanisms are not fully understood. Here the authors show that endothelial low-density lipoprotein receptor-related protein 1 regulates glucose homeostasis via osteocalcin expression.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/1 / 38/77 / 38/91 / 42/44 / 42/89 / 631/443/319/1642/137/1418 / 631/80/86/2371 / 64/60 / 692/163/2743/137/773 / 82/51 / 82/83 / 96/106 / 96/109 / Animal models / Animals / Aorta / Biomedical materials / Capillaries / Coronary vessels / Density / Depletion / Diabetes mellitus / Endothelial Cells / Endothelial Cells - metabolism / Endothelial Cells - pathology / Endothelium / Endothelium, Vascular / Endothelium, Vascular - metabolism / Endothelium, Vascular - pathology / Energy metabolism / Fluorescence / Forkhead Box Protein O1 / Forkhead Box Protein O1 - genetics / Forkhead Box Protein O1 - metabolism / Forkhead protein / Gene Expression Regulation / Genes, Reporter / Glucose / Glucose - metabolism / Glucose Tolerance Test / Green fluorescent protein / Green Fluorescent Proteins / Green Fluorescent Proteins - genetics / Green Fluorescent Proteins - metabolism / HEK293 Cells / Homeostasis / Humanities and Social Sciences / Humans / Hyperglycemia / Hyperglycemia - genetics / Hyperglycemia - metabolism / Hyperglycemia - pathology / Insulin / Insulin - metabolism / Insulin Receptor Substrate Proteins / Insulin Receptor Substrate Proteins - genetics / Insulin Receptor Substrate Proteins - metabolism / Insulin resistance / Insulin-Secreting Cells / Insulin-Secreting Cells - metabolism / Insulin-Secreting Cells - pathology / Lipoproteins / Low Density Lipoprotein Receptor-Related Protein-1 / Low Density Lipoprotein Receptor-Related Protein-1 - deficiency / Low Density Lipoprotein Receptor-Related Protein-1 - genetics / Low density lipoprotein receptors / Male / Metabolism / Mice / Mice, Knockout / multidisciplinary / Muscles / Organs / Osteoblasts / Osteoblasts - metabolism / Osteoblasts - pathology / Osteocalcin / Osteocalcin - genetics / Osteocalcin - metabolism / Paracrine signalling / Proteins / Proto-Oncogene Proteins c-akt / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Q / Receptor density / Receptor, IGF Type 1 / Receptor, IGF Type 1 - genetics / Receptor, IGF Type 1 - metabolism / Receptors / Receptors, G-Protein-Coupled / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Skeletal muscle / Transgenic mice