Endothelial Angpt2 Promotes Adipocyte Progenitor Cells Maturation to Increase Visceral Adipose Tissue Accumulation

IF 4.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes/Metabolism Research and Reviews Pub Date : 2024-12-03 DOI:10.1002/dmrr.70012

Xianhao Yi, Jiapu Ling, Yan Tang, Jingjing Cai, Shaihong Zhu, Liyong Zhu

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Abstract

Aims

Visceral adipose tissue (VAT) accumulation is essential for the occurrence and development of obesity and related metabolic diseases. Currently, the specific mechanism of VAT accumulation is still unclear.

Materials and Methods

We searched the Gene Expression Omnibus database to obtain single-cell RNA sequencing (scRNAseq) data for VAT in patients with a normal body mass index (BMI), obesity, or morbid obesity. By using PCR, WB, immunofluorescence staining, and flow cytometry analysis, we validated the interactions between macrophages, endothelial cells (ECs), and adipocyte progenitor cells (APCs), as well as the underlying mechanism, in VAT. Finally, we tested the findings in obese mice using recombinant proteins and adeno-associated virus infection.

Results

One study with human scRNAseq data was included. This study collected 13-VAT from 5 individuals with obesity and diabetes, 9 individuals with obesity, and 1 individual with a normal BMI. The proportion of inflammatory macrophages is substantially increased in obese and diabetic patients. ECs have the most active interactions with other cells. Notably, the activation of JAK1/STAT3 is one of the reasons for the increase in inflammatory endothelial cells and can promote the secretion of angiopoietin-2 (Angpt2) and induce APCs to transition from mesothelin (MSLN) to complement factor D (CFD) expression via integrin-α5β1 signalling. This phenotypic transition promotes APC differentiation into mature adipocytes and accelerates VAT accumulation. These observations were further validated in an in vitro model and an in vivo study using Angpt2 recombinant proteins and blocking the expression of Angpt2 by adeno-associated virus infection.

Conclusions

ECs are essential for promoting VAT accumulation by facilitating APC differentiation from MSLN to CFD phenotype. This process is driven by Angpt2 from ECs upon JAK1/STAT3 signalling activation under metabolic stress.

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内皮细胞Angpt2促进脂肪祖细胞成熟，增加内脏脂肪组织积累

目的内脏脂肪组织（VAT）的积累是肥胖及相关代谢性疾病发生发展的必要条件。目前，增值税累加的具体机制尚不清楚。材料和方法我们检索了基因表达综合数据库，以获得正常体重指数（BMI）、肥胖或病态肥胖患者的VAT单细胞RNA测序（scRNAseq）数据。通过PCR、WB、免疫荧光染色和流式细胞术分析，我们验证了巨噬细胞、内皮细胞（ECs）和脂肪祖细胞（APCs）在VAT中的相互作用及其潜在机制。最后，我们使用重组蛋白和腺相关病毒感染在肥胖小鼠中测试了这一发现。结果纳入一项人类scRNAseq数据的研究。本研究收集了5例肥胖合并糖尿病患者、9例肥胖患者和1例BMI正常患者的13-VAT数据。在肥胖和糖尿病患者中，炎性巨噬细胞的比例显著增加。内皮细胞与其他细胞的相互作用最为活跃。值得注意的是，JAK1/STAT3的激活是炎性内皮细胞增加的原因之一，可以促进血管生成素-2 （Angpt2）的分泌，并通过整合素-α5β1信号传导诱导apc从间皮素（MSLN）表达转变为补体因子D （CFD）表达。这种表型转变促进APC分化为成熟脂肪细胞并加速VAT积累。使用Angpt2重组蛋白和通过腺相关病毒感染阻断Angpt2表达的体外模型和体内研究进一步验证了这些观察结果。结论ECs通过促进APC从MSLN表型向CFD表型分化而促进VAT积累。这一过程是由代谢应激下ECs中JAK1/STAT3信号激活后的Angpt2驱动的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes/Metabolism Research and Reviews 医学-内分泌学与代谢

CiteScore

17.20

自引率

2.50%

发文量

审稿时长

4-8 weeks

期刊介绍： Diabetes/Metabolism Research and Reviews is a premier endocrinology and metabolism journal esteemed by clinicians and researchers alike. Encompassing a wide spectrum of topics including diabetes, endocrinology, metabolism, and obesity, the journal eagerly accepts submissions ranging from clinical studies to basic and translational research, as well as reviews exploring historical progress, controversial issues, and prominent opinions in the field. Join us in advancing knowledge and understanding in the realm of diabetes and metabolism.