Endothelial metabolic control of insulin sensitivity through resident macrophages
Jing Zhang, Kim A. Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte G. Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E. Dale Abel, Shigeyuki Kon, Danyvid Olivares–Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael J. Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Köpf, Erik A. Richter, Katrien De Bock
Abstract
Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 ( Glut1 /Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion ( Glut1 ΔEC ) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/ Spp1 ) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1 ΔEC 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 microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.