瑞士联邦理工学院Katrien De Bock团队近期取得重要工作进展，他们研究提出，内皮代谢通过常驻巨噬细胞调控胰岛素敏感性。相关研究成果2024年9月12日在线发表于《细胞—代谢》杂志上。

据介绍，内皮细胞（EC）不仅形成被动的血液导管，而且积极促进营养物质运输和器官稳态。然而，EC在葡萄糖稳态中的作用尚不清楚。

研究人员表明，在骨骼肌中，内皮葡萄糖转运蛋白1（Glut1/Slc2a1）通过肌肉驻留巨噬细胞的血管代谢控制来控制葡萄糖摄取，而不影响经内皮葡萄糖转运。通过基因耗竭（Glut1^ΔEC）或短期高脂肪饮食降低内皮Glut1会增加血管分泌骨桥蛋白（OPN/Spp1）的分泌。

这促进了常驻肌肉巨噬细胞的活化和增殖，从而损害了肌肉胰岛素敏感性。因此，从EC中共同删除Spp1可以防止Glut1^ΔEC小鼠的巨噬细胞积聚并提高胰岛素敏感性。从机制上讲，Glut1依赖的内皮葡萄糖代谢重新连接以丝氨酸代谢依赖的方式增加了OPN。

总之，这一研究阐明了糖酵解内皮如何创造一个微环境，控制驻留肌肉巨噬细胞的表型和功能，并直接将驻留肌肉巨噬细胞与维持肌肉葡萄糖稳态联系起来。

附：英文原文

Title: Endothelial metabolic control of insulin sensitivity through resident macrophages

Author: Jing Zhang, Kim Anker Sjberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E. Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A. Richter, Katrien De Bock

Issue&Volume: 2024-09-12

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 (Glut1ΔEC) 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 Glut1ΔEC 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.

DOI: 10.1016/j.cmet.2024.08.008

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00335-8