Consecutive Positive Feedback Loops Create a Bistable Switch that Controls Preadipocyte-to-Adipocyte Conversion
Consecutive Positive Feedback Loops Create a Bistable Switch that Controls Preadipocyte-to-Adipocyte Conversion
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DOI：
10.1016/j.celrep.2012.08.038
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发表时间：
2012-10-01
期刊：
影响因子：
8.8
通讯作者：
Teruel, Mary N.
中科院分区：
文献类型：
--
作者：
Park, Byung Ouk;Ahrends, Robert;Teruel, Mary N.
脂肪生成，或增殖的前脂肪细胞转化为非分裂的脂肪细胞，是脊椎动物体重维持计划的重要组成部分。目前尚不清楚如何以及何时发生不可逆转变为能够积聚脂质的独特状态。在这里，我们使用单细胞荧光成像显示，一个全或无开关诱导脂质积累发生之前。转化开始于糖皮质激素和cAMP信号将C/EBP β水平提高到临界阈值以上，触发三个连续的正反馈循环：从PPAR γ到C/EBP α，然后到C/EBP β，最后到胰岛素受体。实验和建模表明，这些反馈创建一个强大的，不可逆的过渡到一个终端分化的状态，拒绝短和低幅度的刺激。在分化开关被触发后，胰岛素以分级的方式控制脂肪积累。总而言之，我们的研究引入了一个调控基序，通过参与一系列正反馈循环将细胞锁定在分化状态。
Adipogenesis, or the conversion of proliferating preadipocytes into nondividing adipocytes, is an important part of the vertebrate weight-maintenance program. It is not yet understood how and when an irreversible transition occurs into a distinct state capable of accumulating lipid. Here, we use single-cell fluorescence imaging to show that an all-or-none switch is induced before lipid accumulation occurs. Conversion begins by glucocorticoid and cAMP signals raising C/EBP beta levels above a critical threshold, triggering three consecutive positive feedback loops: from PPAR gamma to C/EBP alpha, then to C/EBP beta, and last to the insulin receptor. Experiments and modeling show that these feedbacks create a robust, irreversible transition to a terminally differentiated state by rejecting short- and low-amplitude stimuli. After the differentiation switch is triggered, insulin controls fat accumulation in a graded fashion. Altogether, our study introduces a regulatory motif that locks cells in a differentiated state by engaging a sequence of positive feedback loops.