Department of Internal Medicine III, University of Giessen, Germany.
Department of Internal Medicine III, University of Giessen, Germany.
Cytokine. 2020 Jan;125:154796. doi: 10.1016/j.cyto.2019.154796. Epub 2019 Aug 24.
Regulation of progranulin in adipocytes and its role in inflammation is poorly understood.
(i) to investigate regulation of progranulin in adipocyte differentiation and adipose tissue compartments, (ii) to address progranulin expression in two murine (C57BL/6) models of inflammation.
Progranulin expression was induced during adipocyte differentiation. Neither estradiol nor testosterone or metabolic stimuli such as glucose and insulin modified progranulin synthesis. Fatty acids, bile acids and incretins GLP-1 and GIP-1 exerted potent and differential effects on progranulin secretion. LPS, TNF and IL6 significantly increased progranulin secretion. TLR9 agonists decreased and TLR1/2, TLR3, TLR5, and TLR2/6 ligands increased progranulin expression. TLR3-mediated progranulin induction was abrogated by inhibitors of NF-κB and PI3K pathways. Progranulin expression between murine epididymal and subcutaneous adipose tissue did not differ in total adipose tissue, in isolated adipocytes or in the stromal-vascular cell fraction (SVC). However, SVC expressed significantly higher levels of progranulin than adipocytes at all sites. In adipocytes, female mice had significantly higher progranulin expression at all sites. An intra-peritoneal LPS challenge in mice did not affect adipose tissue progranulin expression, whereas peritoneal infection by S. aureus increased progranulin expression after 24 h.
There are relevant sex-, site- and cell-specific effects on progranulin gene expression that is induced during adipocyte differentiation and modulated by various inflammatory and metabolic factors. Most importantly, ligands for TLR1/2 and TLR2/6 (recognizing S. aureus) in vitro and infection by S. aureus in vivo induce progranulin expression suggesting a role of adipocytes in protection against infection by gram-positive bacteria.
脂肪细胞中颗粒蛋白聚糖的调节及其在炎症中的作用知之甚少。
(i) 研究颗粒蛋白聚糖在脂肪细胞分化和脂肪组织中的调节作用，(ii) 解决两种炎症的小鼠（C57BL/6）模型中的颗粒蛋白聚糖表达问题。
颗粒蛋白聚糖在脂肪细胞分化过程中被诱导表达。雌激素、睾丸酮或葡萄糖和胰岛素等代谢刺激物均未改变颗粒蛋白聚糖的合成。脂肪酸、胆酸和肠降血糖素 GLP-1 和 GIP-1 对颗粒蛋白聚糖的分泌有强大而不同的影响。LPS、TNF 和 IL6 显著增加了颗粒蛋白聚糖的分泌。TLR9 激动剂降低了 TLR1/2、TLR3、TLR5 和 TLR2/6 配体的表达，TLR3 介导的颗粒蛋白聚糖诱导被 NF-κB 和 PI3K 途径抑制剂阻断。在总脂肪组织、分离的脂肪细胞或基质血管细胞部分（SVC）中，两种小鼠附睾和皮下脂肪组织之间的颗粒蛋白聚糖表达没有差异。然而，SVC 在所有部位的表达水平都显著高于脂肪细胞。在脂肪细胞中，所有部位的雌性小鼠颗粒蛋白聚糖表达水平均显著升高。在小鼠中，腹腔内 LPS 挑战不会影响脂肪组织颗粒蛋白聚糖的表达，而金黄色葡萄球菌腹膜感染后 24 小时会增加颗粒蛋白聚糖的表达。
在脂肪细胞分化过程中诱导的颗粒蛋白聚糖基因表达存在显著的性别、部位和细胞特异性影响，并且受到各种炎症和代谢因素的调节。最重要的是，TLR1/2 和 TLR2/6（识别金黄色葡萄球菌）的配体在体外和金黄色葡萄球菌的体内感染诱导了颗粒蛋白聚糖的表达，这表明脂肪细胞在抵御革兰氏阳性菌感染方面具有重要作用。
