MicroRNA 34a Inhibits Beige and Brown Fat Formation in Obesity in Part by Suppressing Adipocyte Fibroblast Growth Factor 21 Signaling and SIRT1 Function
MicroRNA 34a Inhibits Beige and Brown Fat Formation in Obesity in Part by Suppressing Adipocyte Fibroblast Growth Factor 21 Signaling and SIRT1 Function
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DOI：
10.1128/mcb.00596-14
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发表时间：
2014-11-01
影响因子：
5.3
通讯作者：
Kemper, Jongsook Kim
中科院分区：
文献类型：
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作者：
Fu, Ting;Seok, Sunmi;Kemper, Jongsook Kim
棕色脂肪通过非耦合呼吸产生热量，防止体温过低和肥胖。成年人有棕色脂肪，但数量和活动在肥胖症中大幅减少，原因不明。在这里，我们发现肥胖症中microRNA 34 a（miR-34 a）的升高部分地通过抑制布朗宁激活剂成纤维细胞生长因子21（FGF 21）和SIRT 1来抑制脂肪布朗宁。慢病毒介导的miR-34 a下调可降低饮食诱导肥胖小鼠的肥胖，改善血清特征，增加线粒体DNA拷贝数，并增加BALB/c和C57 BL/6小鼠脂肪组织中的氧化功能。值得注意的是，下调miR-34 a增加了米色脂肪特异性标志物CD 137和布朗宁标志物UCP 1在所有类型的白色脂肪（包括内脏脂肪）中的共表达，并促进了棕色脂肪中额外的布朗宁。从机制上讲，下调miR-34 a增加了FGF 21受体组分FGFR 1和β KL以及SIRT 1的表达，导致PGC-1 α的FGF 21/SIRT 1依赖性脱乙酰化和布朗宁基因Ucp 1、Pgc-1 α和Prdm 16的诱导。重要的是，抗miR-34 a介导的有益作用，包括减少肥胖，可能来自多种组织，因为miR-34 a的下调也改善了肝脏FGF 21信号传导和脂质氧化。这项研究将miR-34 a鉴定为米色和棕色脂肪形成的抑制剂，为治疗肥胖相关疾病提供了潜在的靶点。
Brown fat generates heat through uncoupled respiration, protecting against hypothermia and obesity. Adult humans have brown fat, but the amounts and activities are substantially decreased in obesity, by unknown mechanisms. Here we show that elevated microRNA 34a (miR-34a) in obesity inhibits fat browning in part by suppressing the browning activators fibroblast growth factor 21 (FGF21) and SIRT1. Lentivirus-mediated downregulation of miR-34a in mice with diet-induced obesity reduced adiposity, improved serum profiles, increased the mitochondrial DNA copy number, and increased oxidative function in adipose tissue in both BALB/c and C57BL/6 mice. Remarkably, downregulation of miR-34a increased coexpression of the beige fat-specific marker CD137 and the browning marker UCP1 in all types of white fat, including visceral fat, and promoted additional browning in brown fat. Mechanistically, downregulation of miR-34a increased expression of the FGF21 receptor components, FGFR1 and beta KL, and also that of SIRT1, resulting in FGF21/SIRT1-dependent deacetylation of PGC-1 alpha and induction of the browning genes Ucp1, Pgc-1 alpha, and Prdm16. Importantly, anti-miR-34a-mediated beneficial effects, including decreased adiposity, are likely from multiple tissues, since downregulation of miR-34a also improves hepatic FGF21 signaling and lipid oxidation. This study identifies miR-34a as an inhibitor of beige and brown fat formation, providing a potential target for treating obesity-related diseases.