A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation
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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.
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A mathematical model linking the HPA and metabolic axes describes a way in which circadian glucocorticoid oscillations regulate a transcriptional circuit underlying adipocyte differentiation.
“Similarly, a mathematical model linking the HPA and metabolic axes describes a way in which circadian glucocorticoid oscillations regulate a transcriptional circuit underlying adipocyte differentiation [84], suggesting mechanisms by which conditions that disrupt pulsatile glucocorticoid secretion could lead to obesity.”
From Mathematical Modelling of Endocrine Systems (2019) · cites this paper as [84]
Conditions that disrupt pulsatile glucocorticoid secretion could lead to obesity via mechanisms suggested by the model.
“Similarly, a mathematical model linking the HPA and metabolic axes describes a way in which circadian glucocorticoid oscillations regulate a transcriptional circuit underlying adipocyte differentiation [84], suggesting mechanisms by which conditions that disrupt pulsatile glucocorticoid secretion could lead to obesity.”
From Mathematical Modelling of Endocrine Systems (2019) · cites this paper as [84]
Studies in mice demonstrate that abnormal glucocorticoid dynamics can increase the accumulation of fat mass.
“Obesity is perhaps the best example of this, as studies in mice demonstrate that abnormal glucocorticoid dynamics can increase the accumulation of fat mass ( 67 ).”
From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [67]
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Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD
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Nutrients and the Circadian Clock: A Partnership Controlling Adipose Tissue Function and Health
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TGF-β is insufficient to induce adipocyte state loss without concurrent PPARγ downregulation
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Self-citationEarly enforcement of cell identity by a functional component of the terminally differentiated state
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- Authors
- Bahrami-Nejad, Z., Zhao, M. L., Tholen, S., Hunerdosse, D., Tkach, K. E., van Schie, S., Chung, M., & Teruel, M. N.
- Affiliations
- Stanford University (US)
- Corresponding author
- Teruel, Mary N.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 27
- Issue
- 4
- Pages
- 854-868.e8
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5889123
- OpenAlex
- W2796457593
- Cited by
- 65
- References
- 64
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 8 · 2020: 8 · 2019: 7 · 2018: 5
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- NIH (RO1-DK101743, RO1-DK106241, P50-GM107615, T32-NIH T2HG00044, 1F31DK112570-01A1)
- Stanford BioX Seed Grant
- AHA (16POST2700015)
- DFG (TH2156/1-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- circadian oscillations, adipogenesis, PPARγ, CEBPB, positive feedback, obesity, Cushing's disease, stress, single-cell imaging, adipogenic transcription factors
- MeSH terms
- Animals, Circadian Rhythm, Glucocorticoids, Male, Mice, Inbred C57BL, Transcription, Genetic, Stromal Cells, Adipocytes, CCAAT-Enhancer-Binding Protein-beta, 3T3-L1 Cells, PPAR gamma, Adipogenesis, Mice, Single-Cell Analysis
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