Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin.
Hua MaoLuge LiQiying FanAude AngeliniPradip K SahaCristian CoarfaKimal RajapaksheDimuthu PereraJizhong ChengHuaizhu WuChristie M BallantyneZheng SunLiang XieXinchun PiPublished in: Nature communications (2021)
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.
Keyphrases
- endothelial cells
- insulin resistance
- skeletal muscle
- nitric oxide
- type diabetes
- low density lipoprotein
- binding protein
- high glucose
- signaling pathway
- transcription factor
- quantum dots
- cardiovascular disease
- metabolic syndrome
- vascular endothelial growth factor
- gene expression
- adipose tissue
- dna methylation
- atrial fibrillation
- cell proliferation
- blood pressure
- genome wide
- bone mineral density
- postmenopausal women
- small molecule
- protein protein
- bone loss
- induced pluripotent stem cells
- wild type
- pulmonary arterial hypertension
- label free