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Cited by 38Birth, Development, and HealthAdipose Tissue and MetabolismEpigenetics and DNA Methylation

Excessive Glucocorticoids During Pregnancy Impair Fetal Brown Fat Development and Predispose Offspring to Metabolic Dysfunctions

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Chen, Yan-Ting, Hu, Yun, Yang, Qi-Yuan, Son, Jun Seok, Liu, Xiang-Dong, de Avila, Jeanene M., Zhu, Mei-Jun, Du, Min·2020·Diabetes
DOI 10.2337/db20-0009PMC PMC7372078
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Abstract

Maternal stress during pregnancy exposes fetuses to hyperglucocorticoids, which increases the risk of metabolic dysfunctions in offspring. Despite being a key tissue for maintaining metabolic health, the impacts of maternal excessive glucocorticoids (GC) on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. For testing, pregnant mice were administered dexamethasone (DEX), a synthetic GC, in the last trimester of gestation, when BAT development is the most active. DEX offspring had glucose, insulin resistance, and adiposity and also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, Ppargc1a expression was suppressed, together with reduced mitochondrial density, and the brown progenitor cells sorted from offspring BAT demonstrated attenuated brown adipogenic capacity. Increased DNA methylation in Ppargc1a promoter had a fetal origin; elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor/DNMT3b complex in binding to the Ppargc1a promoter, potentially driving its de novo DNA methylation and transcriptional silencing, which impaired fetal BAT development. In summary, maternal GC exposure during pregnancy increases DNA methylation in the Ppargc1a promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions.

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  • Increased DNA methylation of the Ppargc1a promoter in neonatal BAT and brown adipocyte progenitor cells is linked with attenuated BAT development in response to glucocorticoid over-exposure during gestation.

    “There was also increased DNA methylation of the Ppargc1a promoter in neonatal BAT and brown adipocyte progenitor cells, which was linked with attenuated BAT development in response to glucocorticoid over-exposure during gestation [125].”

    From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [125]

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Authors
Chen, Y.-T., Hu, Y., Yang, Q.-Y., Son, J. S., Liu, X.-D., de Avila, J. M., Zhu, M.-J., & Du, M.
Affiliations
  • Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA
  • Washington State University (US)
  • School of Food Sciences, Washington State University, Pullman, WA
Corresponding author
Du, Min
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2020-05-14
Volume
69
Issue
8
Pages
1662-1674
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db20-0009
PMC
PMC7372078
OpenAlex
W3025798589
Cited by
38
References
5
Citations by year
2026: 5 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 9 · 2021: 9 · 2020: 2
FWCI
5.53
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/content/license (vor, 67 d)
Locations
  • Diabetes (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Foundation for the National Institutes of Health (NIH R01-HD067449)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
maternal glucocorticoids, dexamethasone, fetal programming, PGC-1α, DNA methylation, glucocorticoid receptor, DNMT3B, thermogenesis, energy expenditure, insulin resistance, adiposity, cold sensitivity, epigenetic silencing, maternal stress
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Body Temperature, Adipose Tissue, Brown, Calorimetry, Indirect, Dexamethasone, Energy Metabolism, Female, Flow Cytometry, Glucocorticoids, Glucose Tolerance Test, Insulin Resistance, Mice, Inbred C57BL, Pregnancy, Promoter Regions, Genetic, Blotting, Western, Maternal Exposure, Thermogenesis, Microscopy, Electron, Transmission, Chromatin Immunoprecipitation, Immunoprecipitation, Cell Proliferation, Adiposity, Adipogenesis, Mice

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