Knockdown of VEGF-B improves HFD-induced insulin resistance by enhancing glucose uptake in vascular endothelial cells via the PI3K/Akt pathway.

Vascular endothelial growth factor B (VEGF-B) has been suggested to play a crucial role in regulating whole-body glucose homeostasis. However, the involved mechanisms are not fully understood. This study aimed to elucidate the regulatory effects and mechanisms of VEGF-B on glucose uptake in skeletal muscle, focusing on glucose uptake by skeletal muscle cells and vascular endothelial cells. Our results showed that a high-fat diet (HFD) induced significant increase in VEGF-B expression and decrease in glucose uptake by skeletal muscle, accompanied by elevated serum glucose levels. Interestingly, VEGF-B had no direct effect on glucose uptake by skeletal muscle cells (differentiated C2C12). Instead, VEGF-B inhibited glucose uptake of vascular endothelial cells bEnd.3 and subsequent trans-endothelial glucose transport, ultimately resulting in decreased glucose uptake by skeletal muscle cells. Furthermore, VEGF-B suppressed glucose uptake of vascular endothelial cells by downregulating the expression of glucose transporter 1 (GLUT1) through the VEGFR-PI3K/Akt signaling pathway. In vivo, knockdown of VEGF-B in skeletal muscle increased the HFD-impaired glucose uptake of skeletal muscle and improved the HFD-induced glucose intolerance and insulin resistance. This beneficial effect of VEGF-B knockdown was associated with the elevated expression of GLUT1 in the plasma membrane and the activation of the PI3K/Akt pathway in skeletal muscle. In conclusion, our findings demonstrated that knockdown of VEGF-B improved HFD-induced insulin resistance by enhancing glucose uptake in vascular endothelial cells via the PI3K/Akt pathway. These results highlighted the critical role of VEGF-B in regulating glucose uptake by vascular endothelial cells in skeletal muscle, providing a potential new target for improving obesity-induced glucose homeostasis imbalance.