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Maternal obesity imprints methylation marks in oocytes to drive intergenerational metabolic dysfunction

ABSTRACT: Maternal obesity predisposes offspring to metabolic disease, yet how oocytes transmit this risk remains unclear. In the present study, genome-wide profiling revealed that maternal obesity induces locus-specific DNA methylation changes in oocytes. Of them, a subset of metabolic genes, particularly Hnf1α, Thra, and Pdk4, exhibited persistent transcriptional dysregulation across two successive generations. Notably, aberrant methylation at these loci was erased during embryogenesis but re-established postnatally in both germline and somatic tissues, supporting the concept of “methylation memory”. At single-CpG resolution, we identified methylation landmarks at three metabolic loci that strongly correlated with gene expression. Furthermore, by employing methylation-edited mouse model, we demonstrated that targeted oocyte hypermethylation at Hnf1α enhanced hepatic gluconeogenesis in the offspring, whereas Pdk4 hypermethylation impaired muscle glucose tolerance, both in a female-specific manner. Similarly, the elevated methylation of HNF1A and THRA was observed in oocytes from obese women. In sum, our findings provide direct causal evidence that germline methylation at defined loci can drive metabolic reprogramming across generations, highlighting the pre-conceptional period as a critical window for potential intervention in humans.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE309573 | GEO | 2026/07/30

REPOSITORIES: GEO

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Project description:Slimming is globally prevalent especially in young women, and it may contribute to the metabolic health of their offspring. Whereas some Lamarckian ideas about environmental inheritance have been dismissed, increasing evidence suggest that certain acquired traits can be transmitted to the next generation. It is therefore of great interest to determine how and to what extent a maternal lifestyle change contributes to their offspring. Here we show that enriched environment (EE) induced maternal slimming improves general health and reprograms metabolic gene expression in mice offspring. EE in mothers induced decreased body weight, adiposity, and improved glucose tolerance and insulin sensitivity. Relative to controls, their offspring exhibited improved general health such as reduced fat accumulation, enhanced metabolic parameters as well as glucose tolerance and insulin sensitivity. Maternal slimming altered the expression of 1,732 genes in the liver of offspring, with coherent downregulation of genes involved in lipid and cholesterol biosynthesis. Epigenomic profiling in offspring revealed numerous changes in cytosine methylation depending on maternal slimming, including hypermethylation of several genes involved in lipid biosynthesis, correlated with the downregulation of these genes. Maternal slimming also altered overall transcriptome patterns in mature oocytes, which contributes largely to the metabolic health and gene expression patterns in offspring. Overall, our studies suggest that maternal slimming have a beneficial role in regulating metabolic profiles in offspring, implying that it might be considered as a potential strategy to reverse the global prevalence of obesity and related metabolic syndromes. Examination of the effect of 2 different maternal lifestyles, control and slimming, on the mRNA expression in the mature oocytes of the female mice. Naturally ovulated mature oocytes (MII stage) were collected from 3 control and 3 slimming female F0 founders (3 oocytes per mouse, 9 oocytes for each group).

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Maternal obesity imprints methylation marks in oocytes to drive intergenerational metabolic dysfunction

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