Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, CA, USA.
Department of Anesthesiology, Institute of Anesthesiology and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Nat Metab. 2021 Sep;3(9):1163-1174. doi: 10.1038/s42255-021-00444-1. Epub 2021 Sep 6.
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.
在慢性肥胖中，肝细胞变得对胰岛素不敏感，并对全身代谢产生重要影响。在这里，我们发现，在早期肥胖（高脂肪饮食 4 周）中，肝细胞分泌的外泌体在体外和体内均增强了胰岛素敏感性。这些有益作用归因于富含在这些肝细胞外泌体中的微小 RNA 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 耗竭导致胰岛素敏感性增加。在慢性肥胖（高脂肪饮食 16-18 周）中，肝细胞外泌体促进了胰岛素抵抗状态。这些慢性肥胖的肝细胞外泌体不会直接导致体外胰岛素信号传导受损，但确实促进了巨噬细胞的促炎激活。总之，这些研究表明，在早期肥胖中，肝细胞产生表达高水平胰岛素敏感 miR-3075 的外泌体。在慢性肥胖中，这种代偿作用丧失，来自慢性肥胖小鼠的肝细胞衍生的外泌体促进胰岛素抵抗。
