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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.
Highlights
The vascular endothelium is present within metabolic organs and actively regulates energy metabolism
We discovered that endothelial lipoprotein receptor-related protein 1 (LRP1) depletion improved systemic metabolic homeostasis through increasing lipid metabolism[14]
Our previous studies indicate that endothelial LRP1 is involved in whole-body energy homeostasis by using an EC-specific LRP1 knockout mouse model generated by the cross of LRP1f/f and Tie2Cre+ (LRP1Tie2-/-) mice followed by bone marrow transplantation[14]
Summary
The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. 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 crosstalk of metabolic organs plays a crucial role in glucose and lipid homeostasis, and its dysregulation contributes to the progression of diabetes and insulin resistance[3]. We discovered that endothelial LRP1 depletion improved systemic metabolic homeostasis through increasing lipid metabolism[14] It is not fully understood how endothelial LRP1 regulates glucose homeostasis. We performed RNA sequencing analysis with ECs isolated from LRP1 EC-specific inducible knockout (eKO) mice and identified osteocalcin (OCN, called OCN1, OG1 or Bglap) as one of most upregulated genes in LRP1-depleted ECs. OCN has been recognized as an osteoblast-secreted metabolic hormone[15,16,17,18]. Taken for all, our data support that vascular endothelium exerts endocrine/ paracrine regulation of energy homeostasis and expands the biological importance of this organ in glucose homeostasis
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