Endothelial metabolic control of insulin sensitivity through resident macrophages,Cell Metabolism

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Endothelial metabolic control of insulin sensitivity through resident macrophages
Cell Metabolism ( IF 27.7 ) Pub Date : 2024-09-12 , DOI: 10.1016/j.cmet.2024.08.008
Jing Zhang ₁ , Kim Anker Sjøberg ₂ , Songlin Gong ₁ , Tongtong Wang ₃ , Fengqi Li ₄ , Andrew Kuo ₅ , Stephan Durot ₆ , Adam Majcher ₇ , Raphaela Ardicoglu ₈ , Thibaut Desgeorges ₁ , Charlotte Greta Mann ₁ , Ines Soro Arnáiz ₁ , Gillian Fitzgerald ₁ , Paola Gilardoni ₁ , E Dale Abel ₉ , Shigeyuki Kon ₁₀ , Danyvid Olivares-Villagómez ₁₁ , Nicola Zamboni ₆ , Christian Wolfrum ₃ , Thorsten Hornemann ₇ , Raphael Morscher ₁₂ , Nathalie Tisch ₁ , Bart Ghesquière ₁₃ , Manfred Kopf ₁₄ , Erik A Richter ₂ , Katrien De Bock ₁

Affiliation

Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland.
August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
Laboratory of Translational Nutritional Biology, Department Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zürich, 8603 Zürich, Switzerland.
Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China; Key Laboratory of Immune Response and Immunotherapy, Hefei, China.
Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, Boston, MA, USA.
Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute for Clinical Chemistry, University Hospital, Zürich, Switzerland.
Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland; Laboratory of Molecular and Behavioral Neuroscience, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland.
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Department of Molecular Immunology, Faculty of Pharmaceutical Sciences, Fukuyama University, Fukuyama, Japan.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Pediatric Cancer Metabolism Laboratory, Children`s Research Center, University of Zürich, 8032 Zürich, Switzerland.
Metabolomics Core Facility Leuven, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland.

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.

更新日期：2024-09-12

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