Title | A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Bahrami-Nejad Z, Zhao ML, Tholen S, Hunerdosse D, Tkach KE, van Schie S, Chung M, Teruel MN |
Journal | Cell Metab |
Volume | 27 |
Issue | 4 |
Pagination | 854-868.e8 |
Date Published | 2018 04 03 |
ISSN | 1932-7420 |
Keywords | 3T3-L1 Cells, Adipocytes, Adipogenesis, Animals, CCAAT-Enhancer-Binding Protein-beta, Circadian Rhythm, Glucocorticoids, Male, Mice, Mice, Inbred C57BL, PPAR gamma, Single-Cell Analysis, Stromal Cells, Transcription, Genetic |
Abstract | 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. |
DOI | 10.1016/j.cmet.2018.03.012 |
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Alternate Journal | Cell Metab. |
PubMed ID | 29617644 |
PubMed Central ID | PMC5889123 |
Grant List | F31 DK112570 / DK / NIDDK NIH HHS / United States P50 GM107615 / GM / NIGMS NIH HHS / United States R01 DK101743 / DK / NIDDK NIH HHS / United States R01 DK106241 / DK / NIDDK NIH HHS / United States S10 OD018073 / OD / NIH HHS / United States T32 HG000044 / HG / NHGRI NIH HHS / United States P30 DK116074 / DK / NIDDK NIH HHS / United States |