Transcription factor dynamics reveals a circadian code for fat cell differentiation

Abstract

SUMMARYGlucocorticoid 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. By 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 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 can lead to obesity. Given the ubiquitous nature of oscillating hormone secretion in mammals, the filtering mechanism we uncovered may represent a general temporal control principle for differentiation.HIGHLIGHTWe found that the fraction of differentiated cells is controlled by rhythmic and pulsatile hormone stimulus patterns.Twelve hours is the cutoff point for daily hormone pulse durations below which cells fail to differentiate, arguing for a circadian code for hormone-induced cell differentiation.In addition to fast positive feedback such as between PPARG and CEBPA, the adipogenic transcriptional architecture requires added parallel slow positive feedback to mediate temporal filtering of circadian oscillatory inputs