Influence of long term administration of tofogliflozin on chronic inflammation of visceral adipose tissue in mice with obesity induced by a high-fat diet
Influence of long term administration of tofogliflozin on chronic inflammation of visceral adipose tissue in mice with obesity induced by a high-fat diet
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DOI：
10.1371/journal.pone.0211387
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发表时间：
2019-01
期刊：
影响因子：
3.7
通讯作者：
K. Shirakawa;Wataru Yano;Keisuke Inoue;Yoshinori Katsumata;J. Endo;M. Sano
中科院分区：
文献类型：
--
作者：
K. Shirakawa;Wataru Yano;Keisuke Inoue;Yoshinori Katsumata;J. Endo;M. Sano
我们以前发现，由于高脂饮食（HFD），饮食诱导肥胖（DIO）小鼠内脏脂肪组织（VAT）中分化簇4（CD4）T细胞的衰老加速，这些衰老相关的T细胞通过分泌骨桥蛋白引起内脏脂肪组织的慢性炎症，引起全身胰岛素抵抗。在这项研究中，我们检查了DIO小鼠VAT中慢性炎症和衰老相关T细胞的发展是否通过转换为正常食物（NC）后的长期体重减轻或通过给予钠葡萄糖协同转运蛋白2抑制剂（tofoglilidine）得到改善。野生型小鼠从4周龄开始喂食HFD 26周。在30周龄时，将这些DIO小鼠中的一半转换为具有或不具有0.005%托福格列汀的NC，持续38周。其他小鼠在含或不含0.005%托福格列汀的情况下保持HFD 38周。当DIO小鼠转换为NC时，它们的体重降低至自断奶以来保持NC的小鼠的体重。38周（68周龄）后，VAT的慢性炎症消退，衰老相关T细胞消失。在HFD组中，每只小鼠的碳水化合物摄入量为NC组的一半或更少，并且HFD小鼠中托福格列净效应引起的尿糖排泄量低于NC小鼠。保持HFD的小鼠在VAT中的慢性炎症没有显示出改善，可能是因为由于碳水化合物摄入量低，托福格列汀不能充分促进尿糖排泄。因此，在这些小鼠中未观察到葡萄糖代谢改善或体重减轻。
We previously found that senescence of cluster of differentiation 4 (CD4) T cells is accelerated in the visceral adipose tissue (VAT) of mice with diet-induced obesity (DIO) due to a high-fat diet (HFD), and that these senescent-associated T cells cause chronic inflammation of visceral adipose tissue through secretion of osteopontin, provoking systemic insulin resistance. In this study, we examined whether the development of chronic inflammation and senescence-associated T cells in VAT of DIO mice was improved by long-term weight loss after switching to normal chow (NC) or by administration of a sodium glucose cotransporter 2 inhibitor (tofogliflozin). Wild-type mice were fed an HFD for 26 weeks from 4 weeks old. At 30 weeks of age, half of these DIO mice were switched to NC with or without 0.005% tofogliflozin for 38 weeks. The other mice remained on the HFD with or without 0.005% tofogliflozin for 38 weeks. When DIO mice were switched to NC, their weight decreased to that of mice kept on NC since weaning. After 38 weeks (68 weeks of age), chronic inflammation of the VAT subsided with disappearance of senescence-associated T cells. In the HFD groups, the carbohydrate intake per mouse was half or less of that in the NC group, and urinary glucose excretion by the effect of tofogliflozin was lower in the HFD mice than in the NC mice. Mice that remained on the HFD showed no improvement in chronic inflammation in VAT, possibly because urinary glucose excretion was not sufficiently promoted by tofogliflozin due to the low carbohydrate intake. Thus, no improvement in glucose metabolism or weight loss was observed in these mice.