Endothelial Metabolic Control of Resident Muscle Macrophage Function [scRNA-seq]

Endothelial cells (ECs) not only form passive blood conduits. They actively contribute to nutrient transport and establish an instructive vascular niche to maintain and restore organ homeostasis. The role of the endothelium in the maintenance of muscle glucose homeostasis is however poorly understood. Here we show that, in skeletal muscle, the endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake not via affecting transendothelial glucose transport, but via vascular niche control of muscle resident macrophages. Lowering endothelial glut1 via genetic depletion (glut1EC) or upon short-term high-fat diet increased angiocrine osteopontin (OPN/SPP1) secretion, promoting resident muscle macrophage activation and proliferation which impairs muscle insulin sensitivity. Consequently, co-deleting Spp1 from the endothelium prevented macrophage accumulation, reduced muscle OPN levels, and improved insulin sensitivity in glut1EC mice. Mechanistically, glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a niche that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the development of muscle insulin resistance. To explore how endothelial Glut1 deletion regulates macrophages in skeletal muscle, we sort CD45+CD31- and CD31+CD45- cells from skeletal muscle and subjected them for single cells sequencing.