A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation
A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation
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DOI：
10.1016/j.cmet.2018.03.012
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发表时间：
2018-04-03
期刊：
影响因子：
29
通讯作者：
Teruel, Mary N.
中科院分区：
文献类型：
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作者：
Bahrami-Nejad, Zahra;Zhao, Michael L.;Teruel, Mary N.
糖皮质激素和其他成脂激素在哺乳动物中以昼夜节律振荡的方式分泌。这种昼夜节律振荡模式的丧失与人类的肥胖相关，提出了激素分泌动力学如何影响脂肪细胞分化的有趣问题。使用活的，单细胞成像的关键成脂转录因子CEBPB和PPARG，内源性标记的荧光蛋白，我们表明，脉动的昼夜节律激素刺激被拒绝的脂肪细胞分化控制系统。与此形成鲜明对比的是，同样强的持续信号触发了最大的分化。我们确定的机制，如何激素振荡过滤的组合，以PPARG为中心的缓慢和快速的正反馈。此外，我们证实，在小鼠中，平坦的每日糖皮质激素振荡显着增加皮下和内脏脂肪垫的质量。总之，我们的研究为为什么压力、库欣病和其他糖皮质激素分泌失去脉动性的疾病可能导致肥胖提供了分子机制。
Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern correlates with obesity in humans, raising the intriguing question of how hormone secretion dynamics affect adipocyte differentiation. Using live, single-cell imaging of the key adipogenic transcription factors CEBPB and PPARG, endogenously tagged with fluorescent proteins, we show that pulsatile circadian hormone stimuli are rejected by the adipocyte differentiation control system. In striking contrast, equally strong persistent signals trigger maximal differentiation. We identify the mechanism of how hormone oscillations are filtered as a combination of slow and fast positive feedback centered on PPARG. Furthermore, we confirm in mice that flattening of daily glucocorticoid oscillations significantly increases the mass of subcutaneous and visceral fat pads. Together, our study provides a molecular mechanism for why stress, Cushing's disease, and other conditions for which glucocorticoid secretion loses its pulsatility may lead to obesity.