Paternally multi-generational high-fat diet causes obesity and metabolic disorder through intergenerational DNA methylation
Open accessAbstract
Objective: Paternal high-fat diet (HFD) has detrimental effects on offspring. However, the extent of comprehensive damage and the underlying mechanisms associated with sustained multigenerational HFD exposure remain unclear. This study aims to investigate intergenerational progressive accumulation of obesity and glycolipid metabolic disorders, as well as mechanisms mediated by DNA methylation. Methods: We performed a novel paternally multi-generational HFD consumption model in male C57BL/6 J mice, while excluding maternal gestational effects and any confounding influences from females. The body weight and glycolipid metabolism indicators of each generation of male mice were determined. The intergenerational transmission of CpG methylation and gene expression variation was detected through mRNA microarray, methylated DNA immunoprecipitation (MeDIP)-chip, bisulfite sequencing, RT-qPCR, and Western blot etc. Analysis, to indicate genes involved in glycolipid metabolism related to the intergenerational reprogramming. Results: The HFD caused intergenerational accumulation of body weight increase, disturbance of glycolipid metabolism, and insulin insensitivity in male offspring. MeDIP/gene-chip results indicated that paternal HFD significantly modified gene expression and DNA methylation profiles in the liver and sperm of offspring. The majority of differential genes exhibited hypermethylation in promoter regions and reduced expression in the liver, which were linked to the glucolipid metabolic signaling pathway. The elevated promoter methylation and expression states of Spns2 , Lonp1, and Hk1 , which are involved in glycolipid metabolism, were inherited by offspring. Conclusion: This research shows that paternal sustained multi-generational HFD could induce intergenerational progressive accumulation of obesity and metabolic disorder through DNA methylation regulation, and identifies the target genes related to the intergenerational reprogramming, which provides new insights for the establishment of healthy diets and lifestyles.
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Both maternal and paternal nutritional environments before and during conception can profoundly influence offspring metabolic programming through heritable epigenetic mechanisms.
“Together, these findings demonstrate that both maternal and paternal nutritional environments before and during conception can profoundly influence offspring metabolic programming through heritable epigenetic mechanisms.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [177]
The Introduction and Discussion (pages unavailable) link parental high-fat diets to offspring metabolic changes and describe epigenetic inheritance as a possible mechanism. The paper studies paternal exposure, however, and explicitly says maternal-diet findings are confounded by direct exposure in utero; it does not demonstrate that both maternal and paternal effects are transmitted through heritable epigenetic mechanisms. (LLM, conf=0.84)
Experimental — accuracy not yet measuredEmerging evidence indicates that paternal factors also contribute to fetal programming through epigenetic modifications in sperm.
“While much focus has been placed on maternal influences, emerging evidence indicates that paternal factors also contribute to fetal programming through epigenetic modifications in sperm [73,177].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [177]
Parental health and diet, not only during pregnancy but also prior to conception, play a crucial role in shaping disease susceptibility across generations.
“The concept of transgenerational inheritance thus expands the traditional view of fetal programming, emphasizing that parental health and diet—not only during pregnancy but also prior to conception—play a crucial role in shaping disease susceptibility across generations [73,169,175,177,178,179].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [177]
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- Authors
- Guo, T., Hu, Z., Bao, L., Cao, Y., Chu, Z., Wang, M., Li, Y., & Luo, F.
- Affiliations
- Changzhi Medical College (CN)
- Central South University of Forestry and Technology (CN)
- Corresponding author
- Luo, Feijun
- Venue
- Frontiers in Nutrition
- Publisher
- Frontiers Media SA
- Published
- 2025-10-27
- Volume
- 12
- Pages
- 1680793-1680793
- ISSN
- 2296-861X (ISSN-L)
- PMC
- PMC12597747
- OpenAlex
- W4415566207
- Cited by
- 7
- References
- 59
- Citations by year
- 2026: 7
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Nutrition (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- intergenerational epigenetic inheritance, DNA methylation, obesity, glycolipid metabolism, insulin resistance, sperm DNA methylation, hepatic gene expression, SPNS2, LONP1, hexokinase 1, epigenetic reprogramming
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