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Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075
Nature Metabolism ( IF 20.8 ) Pub Date : 2021-09-06 , DOI: 10.1038/s42255-021-00444-1
Yudong Ji 1, 2 , Zhenlong Luo 1, 3 , Hong Gao 1 , Felipe Castellani Gomes Dos Reis 1 , Gautam Bandyopadhyay 1 , Zhongmou Jin 4 , Kameswari Ananthakrishnan Manda 1 , Roi Isaac 1 , Meixiang Yang 5, 6 , Wenxian Fu 5, 7 , Wei Ying 1 , Jerrold M Olefsky 1
Affiliation  

In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4 weeks high-fat diet), hepatocytes secrete exosomes that enhance insulin sensitivity both in vitro and in vivo. These beneficial effects were due to exosomal microRNA miR-3075, which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and small interfering RNA depletion of FA2H in adipocytes, myocytes and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16–18 weeks of a high-fat diet), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signalling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes that express high levels of the insulin-sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.



中文翻译:

来自早发性肥胖小鼠的肝细胞衍生外泌体通过 miR-3075 促进胰岛素敏感性

在慢性肥胖症中,肝细胞会产生胰岛素抵抗并对全身代谢产生重要影响。在这里,我们表明,在早发性肥胖(4 周高脂肪饮食)中,肝细胞分泌的外泌体在体外和体内均能增强胰岛素敏感性。这些有益作用是由于富含这些肝细胞外泌体的外泌体 microRNA miR-3075。FA2H 是 miR-3075 的直接靶标,脂肪细胞、肌细胞和原代肝细胞中 FA2H 的小干扰 RNA 消耗导致胰岛素敏感性增加。在慢性肥胖(16-18 周的高脂肪饮食)中,肝细胞外泌体促进胰岛素抵抗状态。这些慢性肥胖肝细胞外泌体在体外不会直接导致胰岛素信号传导受损,但会促进巨噬细胞的促炎激活。综合起来,这些研究表明,在早发性肥胖中,肝细胞产生的外泌体表达高水平的胰岛素敏化 miR-3075。在慢性肥胖中,这种补偿作用会丧失,并且来自慢性肥胖小鼠的肝细胞来源的外泌体会促进胰岛素抵抗。

更新日期:2021-09-06
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