Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance.
Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance.
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DOI：
10.1016/j.celrep.2018.01.074
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发表时间：
2018-02-20
期刊：
影响因子：
8.8
通讯作者：
Fernández-Hernando C
中科院分区：
文献类型：
--
作者：
Price NL;Singh AK;Rotllan N;Goedeke L;Wing A;Canfrán-Duque A;Diaz-Ruiz A;Araldi E;Baldán Á;Camporez JP;Suárez Y;Rodeheffer MS;Shulman GI;de Cabo R;Fernández-Hernando C
虽然mirna的治疗性调节为许多疾病提供了一种有希望的方法，但mirna的混杂性引起了对有害脱靶效应的关注。miR-33已成为治疗心血管疾病的可能靶点。然而，长期抗miR-33治疗的有害影响以及miR-33−/−小鼠对肥胖和代谢功能障碍的易感性，说明了基于mirna的治疗可能存在的缺陷。我们的工作提供了对miR-33−/−小鼠的深入表征，并探索了miR-33缺失促进关键代谢组织中胰岛素抵抗的机制。与之前的报道相反，我们的数据不支持srebp -1介导的脂质合成在促进这些作用中的直接作用。另外，在miR-33−/−小鼠的脂肪组织中，我们观察到脂肪前细胞增殖增加，脂质摄取增强，脂肪分解受损。此外，我们证明了这些异常背后的驱动力是增加的食物摄入量，这可以通过与野生型动物配对喂养来预防。虽然抗miR-33疗法为治疗心血管疾病提供了希望，但miR-33的缺失会导致肥胖和代谢功能障碍。Price等人阐明了miR-33缺乏如何影响不同组织的代谢功能。他们并没有发现srebp -1介导的脂质合成失调主要驱动了这些影响，而是证明了这些变化取决于食物消耗的增加。
While therapeutic modulation of miRNAs provides a promising approach for numerous diseases, the promiscuous nature of miRNAs raises concern over detrimental off-target effects. miR-33 has emerged as a likely target for treatment of cardiovascular diseases. However, the deleterious effects of long-term anti-miR-33 therapies and predisposition of miR-33−/− mice to obesity and metabolic dysfunction exemplify the possible pitfalls of miRNA-based therapies. Our work provides an in-depth characterization of miR-33−/− mice and explores the mechanisms by which loss of miR-33 promotes insulin resistance in key metabolic tissues. Contrary to previous reports, our data do not support a direct role for SREBP-1-mediated lipid synthesis in promoting these effects. Alternatively, in adipose tissue of miR-33−/− mice, we observe increased pre-adipocyte proliferation, enhanced lipid uptake, and impaired lipolysis. Moreover, we demonstrate that the driving force behind these abnormalities is increased food intake, which can be prevented by pair feeding with wild-type animals. While anti-miR-33 therapies offer promise for treating cardiovascular disease, deletion of miR-33 causes obesity and metabolic dysfunction. Price et al. elucidate how miR-33 deficiency affects metabolic functions in different tissues. Rather than finding that dysregulation of SREBP-1-mediated lipid synthesis primarily drives these effects, they demonstrate that these changes depend on increased food consumption.
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影响因子：
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影响因子：
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影响因子：
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作者：
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