Loss of MyoD Promotes Fate Transdifferentiation of Myoblasts Into Brown Adipocytes.
Loss of MyoD Promotes Fate Transdifferentiation of Myoblasts Into Brown Adipocytes.
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DOI：
10.1016/j.ebiom.2017.01.015
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Kuang S
中科院分区：
文献类型：
--
作者：
Wang C;Liu W;Nie Y;Qaher M;Horton HE;Yue F;Asakura A;Kuang S
棕色脂肪组织(BAT)代表着一种很有前途的药物，可以改善肥胖和其他代谢紊乱。然而，蝙蝠的数量随着年龄的增长而减少，蝙蝠缺乏是肥胖者的共同特征。由于棕色脂肪细胞和成肌细胞具有共同的Myf5谱系起源，阐明棕色脂肪细胞与成肌细胞命运选择的分子机制可能会导致新的方法来扩大蝙蝠的质量。在这里，我们认为MyoD是棕色脂肪细胞发育的关键负性调节因子。CRISPR/Cas9介导的C2C12成肌细胞MyoD缺失促进其成脂转分化。MyoD基因敲除下调miR-133，上调miR-133靶标Igf1r，导致PI3K-Akt信号放大。因此，抑制PI3K或Akt可取消MyoD缺失的成肌细胞的成脂基因表达。引人注目的是，MyoD的缺失通过上调Prdm16的表达将卫星细胞来源的原代成肌细胞转化为棕色脂肪细胞。Prdm16是miR-133的靶标，也是棕色脂肪细胞命运的关键决定因素。相反，在棕色前脂肪细胞中强制表达MyoD阻止了棕色脂肪的形成，并上调了肌源性基因的表达。重要的是，miR-133a基因敲除显著减弱了MyoD对棕色脂肪形成的抑制作用。我们的结果表明，MyoD通过上调miR-133来抑制Akt信号和Prdm16，从而成为棕色脂肪细胞发育的负调控因子。MyoD缺失促进成肌细胞成脂转分化。MyoD的过度表达使棕色前脂肪细胞向成肌细胞转分化。MyoD部分通过miR-133抑制棕色脂肪细胞的命运。棕色脂肪燃烧脂肪产生热量，是治疗肥胖症及其相关疾病的一种很有前途的药物。棕色脂肪细胞和肌肉细胞有着共同的起源，但是什么控制了这两种细胞类型的发育分离还不是很清楚。本研究报告抑制肌祖细胞中的MyoD基因可促进其向小鼠棕色脂肪细胞的分化。相反，在棕色脂肪祖细胞中强制表达MyoD会将它们转化为肌肉细胞。这项工作表明，抑制MyoD可能代表着未来在人类中扩大棕色脂肪和减轻肥胖的方向。
Brown adipose tissue (BAT) represents a promising agent to ameliorate obesity and other metabolic disorders. However, the abundance of BAT decreases with age and BAT paucity is a common feature of obese subjects. As brown adipocytes and myoblasts share a common Myf5 lineage origin, elucidating the molecular mechanisms underlying the fate choices of brown adipocytes versus myoblasts may lead to novel approaches to expand BAT mass. Here we identify MyoD as a key negative regulator of brown adipocyte development. CRISPR/CAS9-mediated deletion of MyoD in C2C12 myoblasts facilitates their adipogenic transdifferentiation. MyoD knockout downregulates miR-133 and upregulates the miR-133 target Igf1r, leading to amplification of PI3K–Akt signaling. Accordingly, inhibition of PI3K or Akt abolishes the adipogenic gene expression of MyoD null myoblasts. Strikingly, loss of MyoD converts satellite cell-derived primary myoblasts to brown adipocytes through upregulation of Prdm16, a target of miR-133 and key determinant of brown adipocyte fate. Conversely, forced expression of MyoD in brown preadipocytes blocks brown adipogenesis and upregulates the expression of myogenic genes. Importantly, miR-133a knockout significantly blunts the inhibitory effect of MyoD on brown adipogenesis. Our results establish MyoD as a negative regulator of brown adipocyte development by upregulating miR-133 to suppress Akt signaling and Prdm16. Loss of MyoD facilitates adipogenic transdifferentiation of myoblasts. Overexpression of MyoD transdifferentiate brown preadipocytes to myoblasts. MyoD acts partially through miR-133 to suppress brown adipocyte cell fate. Brown fat burns fat to produce heat, and represents a promising agent to treat obesity and its related disorders. Brown fat cells and muscle cells share a common origin, but what controls the developmental separation of the two cell types is not well understood. This study reports that inhibition of “MyoD” gene in muscle progenitors promotes their differentiation into brown fat cells in mice. Conversely, forced expression of MyoD in brown fat progenitors converts them into muscle cells. This work suggests that inhibition of MyoD may represent a future direction to expand brown fat and alleviate obesity in humans.