Over 40% of microRNAs (miRNAs) are located in introns of protein-coding genes, and many of these intronic miRNAs are co-regulated with their host genes. In such cases of co-regulation, the products of host genes and their intronic miRNAs can cooperate to coordinately regulate biologically important pathways. Therefore, we screened intronic miRNAs dysregulated in the livers of mouse models of obesity to identify previously uncharacterized protein-coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach revealed that expression of both the gene encoding ectodysplasin A (Eda), the causal gene in X-linked hypohidrotic ectodermal dysplasia (XLHED), and its intronic miRNA, miR-676, was increased in the livers of obese mice. Moreover, hepatic EDA expression is increased in obese human subjects and reduced upon weight loss, and its hepatic expression correlates with systemic insulin resistance. We also found that reducing miR-676 expression in db/db mice increases the expression of proteins involved in fatty acid oxidation and reduces the expression of inflammatory signaling components in the liver. Further, we found that Eda expression in mouse liver is controlled via PPARγ and RXR-α, increases in circulation under conditions of obesity, and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. In accordance with these findings, gain- and loss-of-function approaches reveal that liver-derived EDA regulates systemic glucose metabolism, suggesting that EDA is a hepatokine that can contribute to impaired skeletal muscle insulin sensitivity in obesity.

中文翻译：

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microRNA筛选显示，肝ectodysplasin A表达升高可导致肥胖引起的骨骼肌胰岛素抵抗。

超过40％的microRNA（miRNA）位于蛋白质编码基因的内含子中，许多这些内含子miRNA与它们的宿主基因共同调控。在这种共同调节的情况下，宿主基因及其内含子miRNA的产物可以协同调节生物学上重要的途径。因此，我们筛选了肥胖小鼠模型肝脏中失调的内含子miRNA，以鉴定以前未表征的蛋白质编码宿主基因，这可能与肥胖相关的胰岛素抵抗和2型糖尿病的发病机理有关。我们的方法表明，肥胖小鼠的肝脏中，编码ectodysplasin A（Eda）的基因，X连锁的多汗性外胚层发育不良（XLHED）的致病基因及其内含性miRNA miR-676的表达都增加了。而且，在肥胖的人类受试者中，肝EDA表达增加，而在体重减轻时，肝EDA表达降低，并且其肝表达与全身胰岛素抵抗相关。我们还发现减少db / db小鼠中miR-676的表达可增加参与脂肪酸氧化的蛋白质的表达，并减少肝脏中炎症信号成分的表达。此外，我们发现小鼠肝脏中的Eda表达是通过PPARγ和RXR-α控制的，在肥胖条件下血液循环增加，并促进骨骼肌中JRS激活和IRS1的丝氨酸磷酸化抑制。根据这些发现，获得功能和丧失功能的方法表明，肝脏衍生的EDA可以调节全身性葡萄糖代谢，