Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
Cell Metab. 2018 Apr 3;27(4):854-868.e8. doi: 10.1016/j.cmet.2018.03.012.
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.
在哺乳动物中，糖皮质激素和其他脂肪生成激素呈昼夜节律性波动分泌。这种昼夜节律性波动模式的丧失与人类肥胖相关，这就提出了一个有趣的问题，即激素分泌动力学如何影响脂肪细胞分化。本研究通过对关键脂肪生成转录因子 CEBPB 和 PPARG 的内源性荧光蛋白标记的活细胞、单细胞成像，表明脉冲式昼夜节律性激素刺激被脂肪细胞分化控制系统所拒绝。与此形成鲜明对比的是，同样强烈的持续信号触发了最大程度的分化。我们确定了激素波动被过滤的机制，这是一种以 PPARG 为中心的慢正反馈和快正反馈的组合。此外，我们在小鼠中证实，每日糖皮质激素波动的变平显著增加了皮下和内脏脂肪垫的质量。综上所述，本研究为为什么应激、库欣病和其他糖皮质激素分泌失去脉冲性的疾病可能导致肥胖提供了一个分子机制。
