A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation

Publication date: 3 April 2018
Source:Cell Metabolism, Volume 27, Issue 4
Author(s): Zahra Bahrami-Nejad, Michael L. Zhao, Stefan Tholen, Devon Hunerdosse, Karen E. Tkach, Sabine van Schie, Mingyu Chung, Mary N. Teruel
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.

Graphical abstract

Teaser

Bahrami-Nejad et al. elucidate how adipocytes filter out normal pulsatile circadian hormone stimuli, while strong persistent signals trigger differentiation. Flattening of daily glucocorticoid oscillations in mice results in significant increases in fat mass, providing a molecular mechanism for why chronic stress, Cushing's disease, and other conditions that disrupt pulsatile glucocorticoid secretion lead to obesity.


https://ift.tt/2GQVlOm