PT  - JOURNAL ARTICLE
AU  - Bahrami-Nejad, Zahra
AU  - Zhao, Michael L
AU  - Tholen, Stefan
AU  - Hunerdosse, Devon
AU  - Tkach, Karen M
AU  - van Schie, Sabine
AU  - Chung, Mingyu
AU  - Teruel, Mary N
TI  - Transcription factor dynamics reveals a circadian code for fat cell differentiation
AID  - 10.1101/245332
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 245332
4099  - http://biorxiv.org/content/early/2018/01/11/245332.short
4100  - http://biorxiv.org/content/early/2018/01/11/245332.full
AB  - Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern during stress and disease correlates with increased fat mass and obesity in humans, raising the intriguing question of how hormone secretion dynamics affect the process of 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, leading to very low adipocyte differentiation rates. In striking contrast, equally strong persistent signals trigger maximal differentiation. We identify a network that combines fast and slow positive feedback loops as a unique regulatory motif that selectively suppresses differentiation for circadian pulse patterns. Together, our study provides a molecular mechanism for why stress, Cushing's disease, and other conditions for which glucocorticoid secretion loses its pulsatility can lead to obesity. Furthermore, given the ubiquitous nature of oscillating hormone secretion in mammals, the filtering mechanism we uncovered may represent a general temporal control principle for differentiation.