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Regulation of lymphatic function and injury by nitrosative stress in obese mice.
Molecular Metabolism ( IF 8.1 ) Pub Date : 2020-09-14 , DOI: 10.1016/j.molmet.2020.101081
Sonia Rehal 1 , Raghu P Kataru 1 , Geoffrey E Hespe 1 , Jung Eun Baik 1 , Hyeung Ju Park 1 , Catherine Ly 1 , JinYeon Shin 1 , Babak J Mehrara 1
Affiliation  

Objective

Obesity results in lymphatic dysfunction, but the cellular mechanisms that mediate this effect remain largely unknown. Previous studies in obese mice have shown that inducible nitric oxide synthase-expressing (iNOS+) inflammatory cells accumulate around lymphatic vessels. In the current study, we therefore tested the hypothesis that increased expression of iNOS results in nitrosative stress and injury to the lymphatic endothelial cells (LECs). In addition, we tested the hypothesis that lymphatic injury, independent of obesity, can modulate glucose and lipid metabolism.

Methods

We compared the metabolic changes and lymphatic function of wild-type and iNOS knockout mice fed a normal chow or high-fat diet for 16 weeks. To corroborate our in vivo findings, we analyzed the effects of reactive nitrogen species on isolated LECs. Finally, using a genetically engineered mouse model that allows partial ablation of the lymphatic system, we studied the effects of acute lymphatic injury on glucose and lipid metabolism in lean mice.

Results

The mesenteric lymphatic vessels of obese wild-type animals were dilated, leaky, and surrounded by iNOS+ inflammatory cells with resulting increased accumulation of reactive nitrogen species when compared with lean wild-type or obese iNOS knockout animals. These changes in obese wild-type mice were associated with systemic glucose and lipid abnormalities, as well as decreased mesenteric LEC expression of lymphatic-specific genes, including vascular endothelial growth factor receptor 3 (VEGFR-3) and antioxidant genes as compared with lean wild-type or obese iNOS knockout animals. In vitro experiments demonstrated that isolated LECs were more sensitive to reactive nitrogen species than blood endothelial cells, and that this sensitivity was ameliorated by antioxidant therapies. Finally, using mice in which the lymphatics were specifically ablated using diphtheria toxin, we found that the interaction between metabolic abnormalities caused by obesity and lymphatic dysfunction is bidirectional. Targeted partial ablation of mesenteric lymphatic channels of lean mice resulted in increased accumulation of iNOS+ inflammatory cells and increased reactive nitrogen species. Lymphatic ablation also caused marked abnormalities in insulin sensitivity, serum glucose and insulin concentrations, expression of insulin-sensitive genes, lipid metabolism, and significantly increased systemic and mesenteric white adipose tissue (M-WAT) inflammatory responses.

Conclusions

Our studies suggest that increased iNOS production in obese animals plays a key role in regulating lymphatic injury by increasing nitrosative stress. In addition, our studies suggest that obesity-induced lymphatic injury may amplify metabolic abnormalities by increasing systemic and local inflammatory responses and regulating insulin sensitivity. These findings suggest that manipulation of the lymphatic system may represent a novel means of treating metabolic abnormalities associated with obesity.



中文翻译:

肥胖小鼠亚硝化应激对淋巴功能和损伤的调节。

客观的

肥胖会导致淋巴功能障碍,但介导这种效应的细胞机制在很大程度上仍然未知。先前对肥胖小鼠的研究表明,诱导型一氧化氮合酶表达 (iNOS + ) 炎症细胞在淋巴管周围积聚。因此,在目前的研究中,我们测试了 iNOS 表达增加导致亚硝化应激和淋巴管内皮细胞 (LEC) 损伤的假设。此外,我们测试了淋巴损伤,独立于肥胖,可以调节葡萄糖和脂质代谢的假设。

方法

我们比较了喂食正常食物或高脂肪饮食 16 周的野生型和 iNOS 基因敲除小鼠的代谢变化和淋巴功能。为了证实我们的体内发现,我们分析了活性氮对分离的 LEC 的影响。最后,我们使用允许淋巴系统部分消融的基因工程小鼠模型,研究了急性淋巴损伤对瘦小鼠葡萄糖和脂质代谢的影响。

结果

与瘦野生型或肥胖 iNOS 敲除动物相比,肥胖野生型动物的肠系膜淋巴管扩张、渗漏并被 iNOS +炎症细胞包围,导致活性氮物质的积累增加。与瘦野生型小鼠相比,肥胖野生型小鼠的这些变化与全身葡萄糖和脂质异常以及淋巴管特异性基因(包括血管内皮生长因子受体 3(VEGFR-3)和抗氧化基因)的肠系膜 LEC 表达降低有关。 -型或肥胖的 iNOS 基因敲除动物。体外实验表明,与血液内皮细胞相比,分离的 LEC 对活性氮物质更敏感,并且通过抗氧化疗法改善了这种敏感性。最后,使用白喉毒素特异性消融淋巴管的小鼠,我们发现肥胖引起的代谢异常与淋巴功能障碍之间的相互作用是双向的。瘦小鼠肠系膜淋巴管的靶向部分消融导致 iNOS + 的积累增加炎症细胞和增加的活性氮种类。淋巴消融还导致胰岛素敏感性、血清葡萄糖和胰岛素浓度、胰岛素敏感性基因表达、脂质代谢的显着异常,并显着增加全身和肠系膜白色脂肪组织 (M-WAT) 炎症反应。

结论

我们的研究表明,肥胖动物中 iNOS 产生的增加在通过增加亚硝化应激来调节淋巴损伤方面发挥着关键作用。此外,我们的研究表明,肥胖引起的淋巴损伤可能通过增加全身和局部炎症反应以及调节胰岛素敏感性来放大代谢异常。这些发现表明,淋巴系统的操作可能代表一种治疗与肥胖相关的代谢异常的新方法。

更新日期:2020-10-05
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