脂肪组织减少和脂肪营养不良在木糖基转移酶 II 缺乏的小鼠中。
Adipose tissue loss and lipodystrophy in xylosyltransferase II deficient mice.
机构信息
Department of Physiological Sciences, Oklahoma State University, Stillwater, OK, 74078, USA.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
出版信息
Int J Obes (Lond). 2019 Sep;43(9):1783-1794. doi: 10.1038/s41366-019-0324-1. Epub 2019 Feb 18.
BACKGROUND/OBJECTIVES: The cellular and extracellular matrix (ECM) interactions that regulate adipose tissue homeostasis are incompletely understood. Proteoglycans (PGs) and their sulfated glycosaminoglycans (GAGs) provide spatial and temporal signals for ECM organization and interactions with resident cells by impacting growth factor and cytokine activity. Therefore, PGs and their GAGs could be significant to adipose tissue homeostasis. The purpose of this study was to determine the role of ECM sulfated GAGs in adipose tissue homeostasis.
METHODS
Adipose tissue and metabolic homeostasis in mice deficient in xylosyltransferase 2 (Xylt2-/-) were examined by histologic analyses, gene expression analyses, whole body fat composition measurements, and glucose tolerance test. Adipose tissue inflammation and adipocyte precursors were characterized by flow cytometry and in vitro culture of mesenchymal stem cells.
RESULTS
Xylt2-/- mice have low body weight due to overall reductions in abdominal fat deposition. Histologically, the adipocytes are reduced in size and number in both gonadal and mesenteric fat depots of Xylt2-/- mice. In addition, these mice are glucose intolerant, insulin resistant, and have increased serum triglycerides as compared to Xylt2 + / + control mice. Furthermore, the adipose tissue niche has increased inflammatory cells and enrichment of proinflammatory factors IL6 and IL1β, and these mice also have a loss of adipose tissue vascular endothelial cells. Lastly, xylosyltransferease-2 (XylT2) deficient mesenchymal stem cells from gonadal adipose tissue and bone marrow exhibit impaired adipogenic differentiation in vitro.
CONCLUSIONS
Decreased GAGs due to the loss of the key GAG assembly enzyme XylT2 causes reduced steady state adipose tissue stores leading to a unique lipodystrophic model. Accumulation of an adipocytic precursor pool of cells is discovered indicating an interruption in differentiation. Therefore, adipose tissue GAGs are important in the homeostasis of adipose tissue by mediating control of adipose precursor development, tissue inflammation, and vascular development.
背景/目的：调节脂肪组织稳态的细胞和细胞外基质（ECM）相互作用尚未完全阐明。蛋白聚糖（PGs）及其硫酸化糖胺聚糖（GAGs）通过影响生长因子和细胞因子的活性，为 ECM 组织和与驻留细胞的相互作用提供时空信号。因此，PGs 及其 GAGs 可能对脂肪组织稳态具有重要意义。本研究旨在确定 ECM 硫酸化 GAGs 在脂肪组织稳态中的作用。
方法
通过组织学分析、基因表达分析、全身脂肪成分测量和葡萄糖耐量试验，检查 Xylosyltransferase 2（Xylt2-/-）缺乏的小鼠的脂肪组织和代谢稳态。通过流式细胞术和间质干细胞体外培养，对脂肪组织炎症和脂肪细胞前体进行了表征。
结果
Xylt2-/-小鼠体重较低，原因是腹部脂肪沉积减少。组织学上，Xylt2-/-小鼠的性腺和肠系膜脂肪组织中脂肪细胞体积和数量减少。此外，与 Xylt2+/+对照小鼠相比，这些小鼠葡萄糖耐量降低，胰岛素抵抗，血清甘油三酯升高。此外，脂肪组织龛位有更多的炎性细胞和促炎因子 IL6 和 IL1β 的富集，这些小鼠也有脂肪组织血管内皮细胞的丢失。最后，来自性腺脂肪组织和骨髓的 Xylosyltransferase-2（XylT2）缺乏的间充质干细胞在体外表现出脂肪生成分化受损。
结论
由于关键 GAG 组装酶 XylT2 的缺失导致 GAG 减少，导致稳态脂肪组织储存减少，导致独特的脂肪营养不良模型。发现脂肪细胞前体细胞池的积累表明分化中断。因此，脂肪组织 GAGs 通过调节脂肪前体细胞发育、组织炎症和血管发育，在脂肪组织稳态中具有重要作用。
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