Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice
Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice
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DOI：
10.1073/pnas.1808855115
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发表时间：
2018-11-27
影响因子：
11.1
通讯作者：
Parrizas, Marcelina
中科院分区：
文献类型：
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作者：
Castano, Carlos;Kalko, Susana;Parrizas, Marcelina
肥胖常常与代谢性疾病有关。在这里，我们发现肥胖改变了小鼠血浆外泌体的miRNA谱，包括miR-122，miR-192，miR-27 a-3 p和miR-27 b-3 p的增加。重要的是，用从肥胖小鼠分离的外泌体治疗瘦小鼠诱导葡萄糖耐受不良和胰岛素抵抗。此外，施用用肥胖相关miRNA模拟物转染的对照外泌体强烈诱导瘦小鼠的葡萄糖耐受不良，并导致向心性肥胖和肝脂肪变性。候选靶基因Ppara的表达在模拟治疗（MIMIC）小鼠的白色脂肪组织中减少，但在肝脏中没有减少，并且伴有循环游离脂肪酸增加和高甘油三酯血症。用靶向转染到外泌体中的Ppara的特异性SiRNA进行治疗，重现了肥胖相关miRNA诱导的表型。重要的是，同时降低脂肪分解抑制剂阿昔莫司或PPARalpha激动剂非诺贝特在MIMIC小鼠中的游离脂肪酸血浆水平可部分保护这些代谢改变。总体而言，我们的数据突出了肥胖相关的外泌体miRNA在葡萄糖耐受不良和血脂异常的发病机制中的核心作用。
Obesity is frequently associated with metabolic disease. Here, we show that obesity changes the miRNA profile of plasma exosomes in mice, including increases in miR-122, miR-192, miR-27a-3p, and miR-27b-3p. Importantly, treatment of lean mice with exosomes isolated from obese mice induces glucose intolerance and insulin resistance. Moreover, administration of control exosomes transfected with obesity-associated miRNA mimics strongly induces glucose intolerance in lean mice and results in central obesity and hepatic steatosis. Expression of the candidate target gene Ppara is decreased in white adipose tissue but not in the liver of mimic-treated (MIMIC) mice, and this is accompanied by increased circulating free fatty acids and hypertriglyceridemia. Treatment with a specific siRNA targeting Ppara transfected into exosomes recapitulates the phenotype induced by obesity-associated miRNAs. Importantly, simultaneously reducing free fatty acid plasma levels in MIMIC mice with either the lipolysis inhibitor acipimox or the PPAR alpha agonist fenofibrate partially protects against these metabolic alterations. Overall, our data highlight the central role of obesity-associated exosomal miRNAs in the etiopathogeny of glucose intolerance and dyslipidemia.