Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy
Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy
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DOI：
10.1172/jci73468
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发表时间：
2014-08-01
影响因子：
15.9
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
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作者：
Mori, Marcelo A.;Thomou, Thomas;Kahn, C. Ronald
miRNA是许多组织中生物学过程的重要调节因子，包括棕色和白色脂肪细胞的分化和功能。内切核糖核酸酶dicer是miRNA加工途径的主要组分，并且在脂肪组织中，dicer的水平已显示出随年龄而降低，随热量限制而增加，并影响应激抗性。在这里，我们证明了具有脂肪特异性切丁酶KO的小鼠发展为一种形式的脂肪营养不良，其特征在于腹内和皮下白色脂肪的损失、严重的胰岛素抵抗以及肩胛间棕色脂肪的增大和“变白”。此外，在培养的棕色前脂肪细胞中敲除dicer促进了白色脂肪细胞样表型，并减少了几种miRNA的表达。棕色前脂肪细胞变白被miR-365的表达部分逆转，miR-365是一种已知促进棕色脂肪分化的miRNA;然而，引入其他miRNA，包括miR-346和miR-362，也有助于逆转dicer表型的丧失。有趣的是，来自HIV相关脂肪营养不良患者的脂肪样本显示出dicer mRNA表达的显著下调。总之，这些发现表明miRNA加工在白色和棕色脂肪组织测定中的重要性，并提供了该过程与HIV相关的脂肪代谢障碍之间的潜在联系。
miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and "whitening" of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte-like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.