Transcription factor Hlx controls a systematic switch from white to brown fat through Prdm16-mediated co-activation.
Transcription factor Hlx controls a systematic switch from white to brown fat through Prdm16-mediated co-activation.
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DOI：
10.1038/s41467-017-00098-2
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发表时间：
2017-07-12
影响因子：
16.6
通讯作者：
Wang YX
中科院分区：
文献类型：
--
作者：
Huang L;Pan D;Chen Q;Zhu LJ;Ou J;Wabitsch M;Wang YX
皮下白色脂肪（iWAT）的褐变涉及多个重编程事件，但其潜在机制尚不完全清楚。在这里，我们表明转录因子 Hlx 在棕色脂肪组织 (BAT) 和 iWAT 中选择性表达，并通过 β3 肾上腺素信号传导介导的翻译抑制剂 4E-BP1 抑制进行翻译上调。 Hlx 与 Prdm16 相互作用并共同激活，以控制 BAT 选择性基因表达和线粒体生物发生。 Hlx杂合基因敲除小鼠在iWAT中存在棕色样脂肪细胞形成缺陷，并出现葡萄糖不耐症和高脂肪诱导的肝脂肪变性。相反，Hlx在生理水平上的转基因表达驱动完整的产热程序，并将iWAT转化为棕色样脂肪，从而改善葡萄糖稳态并预防肥胖和肝脂肪变性。分别通过脂肪特异性注射 Hlx 敲低病毒和过表达病毒来重现脂肪重塑表型。我们的研究证实 Hlx 是系统性白色脂肪组织褐变的强大调节剂，并为潜在的转录机制提供了分子见解。转录共激活因子 Prdm16 调节白色脂肪组织 (WAT) 的褐变。在这里，作者表明 Prdm16 与转录因子 Hlx 相互作用，转录因子 Hlx 在 β3 肾上腺素信号传导的作用下稳定，以增加皮下 WAT 中的产热基因表达和线粒体生物发生。
Browning of subcutaneous white fat (iWAT) involves several reprograming events, but the underlying mechanisms are incompletely understood. Here we show that the transcription factor Hlx is selectively expressed in brown adipose tissue (BAT) and iWAT, and is translationally upregulated by β3-adrenergic signaling-mediated suppression of the translational inhibitor 4E-BP1. Hlx interacts with and is co-activated by Prdm16 to control BAT-selective gene expression and mitochondrial biogenesis. Hlx heterozygous knockout mice have defects in brown-like adipocyte formation in iWAT, and develop glucose intolerance and high fat-induced hepatic steatosis. Conversely, transgenic expression of Hlx at a physiological level drives a full program of thermogenesis and converts iWAT to brown-like fat, which improves glucose homeostasis and prevents obesity and hepatic steatosis. The adipose remodeling phenotypes are recapitulated by fat-specific injection of Hlx knockdown and overexpression viruses, respectively. Our studies establish Hlx as a powerful regulator for systematic white adipose tissue browning and offer molecular insights into the underlying transcriptional mechanism. The transcriptional co-activator Prdm16 regulates browning of white adipose tissue (WAT). Here, the authors show that Prdm16 interacts with the transcription factor Hlx, which is stabilized in response to β3-adrenergic signaling, to increase thermogenic gene expression and mitochondrial biogenesis in subcutaneous WAT.
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影响因子：
29
作者：
Cypess AM;Haft CR;Laughlin MR;Hu HH
通讯作者：
Hu HH
影响因子：
29
作者：
Kajimura S;Spiegelman BM;Seale P
通讯作者：
Seale P
影响因子：
29
作者：
Harms MJ;Ishibashi J;Wang W;Lim HW;Goyama S;Sato T;Kurokawa M;Won KJ;Seale P
通讯作者：
Seale P
影响因子：
64.5
作者：
Cohen P;Levy JD;Zhang Y;Frontini A;Kolodin DP;Svensson KJ;Lo JC;Zeng X;Ye L;Khandekar MJ;Wu J;Gunawardana SC;Banks AS;Camporez JP;Jurczak MJ;Kajimura S;Piston DW;Mathis D;Cinti S;Shulman GI;Seale P;Spiegelman BM
通讯作者：
Spiegelman BM
影响因子：
64.5
作者：
Berger, Michael F.;Badis, Gwenael;Hughes, Timothy R.
通讯作者：
Hughes, Timothy R.