Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin
| Autor: | Jizhong Cheng, Christie M. Ballantyne, Luge Li, Xinchun Pi, Hua Mao, Dimuthu Perera, Zheng Sun, Liang Xie, Pradip K. Saha, Huaizhu Wu, Cristian Coarfa, Kimal Rajapakshe, Aude Angelini, Qiying Fan |
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| Rok vydání: | 2021 |
| Předmět: |
Male
General Physics and Astronomy Receptor IGF Type 1 Receptors G-Protein-Coupled Mice Genes Reporter Insulin-Secreting Cells Insulin Glucose homeostasis Mice Knockout Multidisciplinary biology Forkhead Box Protein O1 Chemistry Type 2 diabetes LRP1 Type 1 diabetes medicine.anatomical_structure Checkpoint signalling Osteocalcin Signal transduction Low Density Lipoprotein Receptor-Related Protein-1 Signal Transduction musculoskeletal diseases Genetically modified mouse medicine.medical_specialty Endothelium Science Green Fluorescent Proteins Article General Biochemistry Genetics and Molecular Biology Paracrine signalling Insulin resistance Internal medicine medicine Animals Humans Osteoblasts Endothelial Cells General Chemistry Glucose Tolerance Test medicine.disease Glucose HEK293 Cells Endocrinology Gene Expression Regulation Hyperglycemia Insulin Receptor Substrate Proteins biology.protein Endothelium Vascular Proto-Oncogene Proteins c-akt |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-25673-6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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