Endothelial Metabolic Control of Insulin Sensitivity Through Resident Macrophages

Endocrinology Rheumatology and Immunology Biochemistry Life Sciences Immunology Medicine Cell Biology
endothelial cells glucose metabolism insulin resistance resident macrophages muscle insulin sensitivity

Endothelial Cells Influence Insulin Sensitivity Through Metabolic Regulation of Resident Macrophages

In recent years, metabolic diseases, especially insulin resistance and diabetes, have become significant global health issues. Muscle tissue, being one of the main organs for glucose metabolism in the human body, has its insulin sensitivity closely related to the maintenance of overall glucose homeostasis. However, the factors affecting the insulin sensitivity of muscle tissue are complex and diverse. Besides the metabolic regulation of the muscle cells themselves, the role of other cells in the muscle tissue microenvironment, especially macrophages residing in the muscle, has gradually attracted attention. This paper, published by Jing Zhang et al. in “Cell Metabolism,” titled “Endothelial Metabolic Control of Insulin Sensitivity through Resident Macrophages,” investigates how endothelial cells (Endothelial Cell, EC) influence muscle insulin sensitivity through the metabolic regulation of resident macrophages.

I. Research Background and Problem Statement

It is well known that endothelial cells are not only components of blood vessels but also play an essential role in the transport of metabolites and the maintenance of organ homeostasis. However, current understanding of the role of endothelial cells in glucose homeostasis is still limited. The authors point out that although muscle endothelial cells express the glucose transporter protein GLUT1, it is not yet clear whether they make a significant contribution to muscle glucose uptake. Additionally, macrophages residing in muscle play a crucial role in maintaining muscle homeostasis, not only by clearing damaged cells to maintain tissue integrity but also in regulating metabolic signals. Based on this, the study aims to explore how the metabolic state of endothelial cells can influence insulin sensitivity by regulating resident macrophages in the muscle.

II. Source and Methods of the Study

This study was conducted by researchers from prestigious institutions such as ETH Zurich, University of Copenhagen, and Harvard Medical School, published in the November 2024 issue of “Cell Metabolism.” The research team utilized various genetically modified mouse models, metabolomics analysis, flow cytometry, and RNA sequencing to comprehensively study the role of endothelial cell GLUT1 in muscle tissue.

III. Research Process

  1. Construction of Endothelial Cell GLUT1 Knockout Model: The research team constructed endothelial cell-specific GLUT1 knockout mice (GLUT1^DEC) and found that this knockout did not affect vascular structure and permeability. To investigate whether GLUT1 participates in trans-endothelial glucose transport, the team conducted glucose clamp experiments, which showed that GLUT1 knockout did not affect muscle glucose uptake, indicating that GLUT1 may not be the decisive factor for muscle glucose transport.

  2. Impact on Resident Macrophage Phenotype and Function: Further analysis showed that the knockout of GLUT1 significantly increased the number of resident macrophages near the blood vessels. Flow cytometry analysis revealed that these resident macrophages exhibited characteristics of low MHC II expression and high Lyve1 and Timd4 expression, consistent with an embryonic-derived macrophage subpopulation phenotype. This group showed significant proliferation and activation after GLUT1 knockout.

  3. Regulatory Mechanism of Resident Macrophages: To further understand how GLUT1 knockout induces macrophage proliferation and activation, the research team conducted RNA sequencing analysis. The results showed significant enrichment of inflammation responses and leukocyte activation-related pathways in GLUT1 knockout endothelial cells. Additionally, the study found that GLUT1 knockout increased the secretion of a protein called Osteopontin (OPN). Through experiments, the authors confirmed that the metabolic reprogramming induced by GLUT1 knockout in endothelial cells promotes OPN secretion, which further activates and increases resident macrophage numbers.

  4. Inhibition of Resident Macrophages Improves Insulin Sensitivity: By injecting antibodies to inhibit the proliferation of resident macrophages, the research team observed a significant improvement in insulin sensitivity in GLUT1 knockout mice, demonstrating a direct link between macrophage accumulation and insulin resistance.

  5. Link Between OPN and Insulin Sensitivity: To explore the specific mechanism of OPN, the research team further constructed a double knockout model (GLUT1/Spp1^DEC), in which both GLUT1 and OPN were knocked out. The results showed that the absence of OPN completely prevented the proliferation of resident macrophages and restored muscle insulin sensitivity. This indicates that OPN is a key factor in GLUT1 metabolic reprogramming-induced macrophage proliferation and insulin resistance.

IV. Research Findings

The main findings of the study are as follows:

  • Metabolic Reprogramming of GLUT1: After GLUT1 knockout, the glucose metabolism of endothelial cells undergoes reprogramming, with metabolic pathways shifting from downstream glycolysis to alternative routes that support OPN secretion, such as the pentose phosphate pathway and serine synthesis pathway. The study shows that GLUT1 knockout triggers the secretion of OPN, a process dependent on serine metabolism.

  • Regulatory Role of OPN on Resident Macrophages: OPN secreted by endothelial cells binds to the Itga9 receptor, activating and promoting the proliferation and phenotype transformation of resident macrophages, thereby affecting insulin sensitivity.

  • Impact of Resident Macrophages on Insulin Resistance: Macrophages residing in muscle accumulate and activate under GLUT1 knockout conditions, further reducing muscle insulin sensitivity through the release of inflammatory cytokines.

V. Conclusion and Significance of the Study

The study elucidates how endothelial cells in muscle tissue regulate the phenotype and function of resident macrophages through their metabolic state, thus affecting insulin sensitivity. The research reveals a novel metabolic regulation mechanism where GLUT1 influences OPN secretion through metabolic reprogramming, subsequently regulating the accumulation and activation of resident macrophages. This discovery holds significant importance, not only broadening our understanding of metabolic diseases but also providing new targets for intervention in insulin resistance.

VI. Highlights and Innovations of the Study

  1. Metabolic Regulatory Role of Endothelial Cells: Traditionally, endothelial cells have been seen as passive components of blood vessels. This study demonstrates their active role in glucose homeostasis and metabolic regulation.

  2. Discovery of a New Metabolic-Immune Interaction Mechanism: The study reveals a mechanism where endothelial cells regulate insulin sensitivity through OPN influencing resident macrophages, providing a new perspective for studying metabolic diseases.

  3. Provision of Potential Therapeutic Targets: The relationship between endothelial cell GLUT1 and OPN and its impact on resident macrophages provides potential targets for treating metabolic diseases, particularly insulin resistance.

VII. Limitations and Future Prospects

The authors note that this study used in vitro bone marrow-derived macrophages for some experiments, a model that may not fully replicate the characteristics of macrophages residing in specific tissues. Additionally, while the study focuses on the interaction between endothelial cells and macrophages in muscle tissue, similar mechanisms in other tissues remain to be verified.

Future research could explore whether such interactions between endothelial cells and resident macrophages exist in other tissues and whether they are related to other pathological processes, such as immune regulation in the tumor microenvironment. Furthermore, future studies might investigate whether other secreted factors from endothelial cells similarly affect tissue homeostasis and metabolic regulation.

Summary

This paper explores the role of muscle endothelial cell GLUT1 from a metabolic regulation perspective, revealing a mechanism by which it influences insulin sensitivity through the secretion of OPN and regulation of resident macrophages. This study not only broadens our understanding of the role of endothelial cells in metabolic diseases but also provides potential therapeutic targets for future interventions in metabolic diseases.