Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner
Open accessAbstract
OBJECTIVE: According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner. We hypothesized that leptin upregulation occurs via epigenetic malprogramming, which takes place early during development of WAT. METHODS: two potential enhancers located upstream and downstream of the leptin transcription start site that exhibit strong dynamic epigenomic remodeling during adipocyte differentiation. We then focused on epigenetic modifications (methylation, hydroxymethylation, and histone modifications) of the promoter and the two potential enhancers regulating leptin gene expression in perirenal (pWAT) and inguinal (iWAT) fat pads of HF offspring during lactation (postnatal days 12 (PND12) and 21 (PND21)) and in adulthood. RESULTS: PND12 is an active period for epigenomic remodeling in both deposits especially in the upstream enhancer, consistent with leptin gene induction during adipogenesis. Unlike iWAT, some of these epigenetic marks were still observable in pWAT of weaned HF offspring. Retained marks were only visible in pWAT of 9-month-old HF rats that showed a persistent "expandable" phenotype. CONCLUSIONS: Consistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions especially within intergenic sequences, linked to higher leptin gene expression in adult HF offspring in a depot-specific manner.
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Maternal obesity is associated with increased H3K4me1/H3K27ac histone modifications in enhancer sites upstream of the leptin gene, which correlates with enhanced leptin expression in the WAT of male offspring.
“Of note, maternal obesity was associated with increased H3K4me1/H3K27ac histone modifications in enhancer sites upstream of the leptin gene, which correlated with enhanced leptin expression in the WAT of male offspring [143].”
From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [143]
The Results section on the upstream enhancer reports higher H3K27ac in offspring of obese dams and correlates the epigenetic changes with leptin mRNA levels. It describes H3K4me1 enrichment only as a tendency, however, and says the changes persisted in perirenal WAT but not inguinal WAT; the citing sentence presents the increase more definitively and without that depot distinction. Page numbers are unavailable in our copy. (LLM, conf=0.84)
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Developmental programming of offspring adipose tissue biology and obesity risk
Rodgers, A., & Sferruzzi-Perri, A. N. (2021) · International Journal of Obesity · doi:10.1038/s41366-021-00790-w · Cited by 57 · see citing works
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- Authors
- Lecoutre, S., Oger, F., Pourpe, C., Butruille, L., Marousez, L., Dickes-Coopman, A., Laborie, C., Guinez, C., Lesage, J., Vieau, D., Junien, C., Eberlé, D., Gabory, A., Eeckhoute, J., & Breton, C.
- Affiliations
- Université de Lille (FR)
- École Nationale Vétérinaire d'Alfort (FR)
- Université Paris-Saclay (FR)
- Inserm (FR)
- Corresponding author
- Breton, Christophe
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 6
- Issue
- 8
- Pages
- 922-930
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC5518658
- OpenAlex
- W2620928092
- Cited by
- 49
- References
- 54
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 10 · 2018: 6 · 2017: 1
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion, other-oa)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale (ANR-10-LABX-46, DEQ20150331724)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- maternal obesity, leptin gene expression, epigenetic modifications, developmental programming, white adipose tissue, perirenal fat, inguinal adipose tissue, adipogenesis, lactation, DNA methylation, histone modifications, hydroxymethylation, enhancers, high-fat diet, adipocyte hypertrophy, intergenerational programs
- MeSH terms
- Animals, Female, Male, Obesity, Pregnancy, Pregnancy Complications, Up-Regulation, Rats, Wistar, DNA Methylation, Leptin, Histone Code, Epigenesis, Genetic, Rats, Adipose Tissue, White
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