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

TitleEndothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin.
Publication TypeJournal Article
Year of Publication2021
AuthorsMao H, Li L, Fan Q, Angelini A, Saha PK, Coarfa C, Rajapakshe K, Perera D, Cheng J, Wu H, Ballantyne CM, Sun Z, Xie L, Pi X
JournalNat Commun
Volume12
Issue1
Pagination5296
Date Published2021 09 06
ISSN2041-1723
KeywordsAnimals, 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
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.

DOI10.1038/s41467-021-25673-6
Alternate JournalNat Commun
PubMed ID34489478
PubMed Central IDPMC8421392
Grant ListR01 HL061656 / HL / NHLBI NIH HHS / United States
R01 DK121348 / DK / NIDDK NIH HHS / United States
R01 HL122736 / HL / NHLBI NIH HHS / United States
P42 ES027725 / ES / NIEHS NIH HHS / United States
R01 DK111436 / DK / NIDDK NIH HHS / United States
R01 DK123186 / DK / NIDDK NIH HHS / United States
R01 DK114356 / DK / NIDDK NIH HHS / United States
R01 ES027544 / ES / NIEHS NIH HHS / United States
R21 CA215591 / CA / NCI NIH HHS / United States
P30 ES030285 / ES / NIEHS NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
UM1 HG006348 / HG / NHGRI NIH HHS / United States
R01 HL153320 / HL / NHLBI NIH HHS / United States
R01 HL112890 / HL / NHLBI NIH HHS / United States