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Maternal obesity alters offspring liver and skeletal muscle metabolism in early post-puberty despite maintaining a normal post-weaning dietary lifestyle

ABSTRACT: Maternal obesity (MO) during pregnancy is linked to increased and premature risk of age-related metabolic diseases in the offspring. However, the underlying molecular mechanisms still remain not fully understood. Using a well-established baboon model of MO, we analyzed tissue biopsies and plasma samples obtained from post-pubertal offspring (3-6.5y at sample collection) of MO mothers (n=19) and from control animals born to mothers fed a standard diet (CON, n=13). All offspring ate normal chow diet after weaning. With an untargeted gas chromatography-mass spectrometry metabolomics profiling, we quantified a total of 351 liver, 316 skeletal muscle and 423 plasma metabolites. We found 58 metabolites significantly altered in liver and 46 in skeletal muscle of MO offspring, including 8 metabolites shared between both tissues. Male and female-specific metabolites in opposite direction of change were found in liver and skeletal muscle of MO offspring. Several tissue-specific and 4 shared metabolic pathways were identified from these dysregulated metabolites. Interestingly, none of the tissue-specific metabolic alterations reflected in plasma. Our results identify tissue metabolites and pathways in post-pubertal MO offspring in a sex-specific manner.

ORGANISM(S): Papio Hamadryas Baboon

TISSUE(S): Liver, Muscle, Blood

DISEASE(S): Obesity

SUBMITTER: Isaac Ampong

PROVIDER: ST002254 | MetabolomicsWorkbench | Tue Aug 02 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Background: Consumption of high fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in mouse offspring fed a high fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Results: Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Conclusions: Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets during gestation and lactation can alter global DNA methylation in liver. This may be one mechanism by which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health. Female wild type C57BL/6 mice (Animal Resource Centre, Western Australia) were fed a High Fat diet containing low levels of selenium and folate (HF-Low) for 7 days prior to mating with male C57BL/6 mice (Ruakura Small Animal Facility, Hamilton, New Zealand). Mothers were maintained on the HF-Low diet throughout gestation and lactation. Offspring of these female mice were randomly assigned to one of two different dietary treatments: either the same diet as the mothers (HF-Low), or a High Fat diet containing adequate selenium and folate (HF-Suf). At 12 weeks of age, mice were euthanized and colon and liver samples taken for microarray, proteomics, and DNA methylation analyses. Genomic DNA, total RNA and protein from whole colon and liver tissue was extracted using an AllPrepM-BM-. DNA/RNA/Protein mini kit (Qiagen, Cat number 80004). Colon and liver RNA from six female offspring on the HF-Low diet was compared with colon and liver RNA from six female offspring on the HF-Suf diet. All individual RNA samples were hybridized against a common reference RNA on separate arrays. The reference RNA was prepared by pooling in equimolar proportions RNA extracted from the intestine and liver of twelve female C57BL/6 mice, these being all of the mice from which samples were derived for microarray analysis in the current study.

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Maternal obesity alters offspring liver and skeletal muscle metabolism in early post-puberty despite maintaining a normal post-weaning dietary lifestyle

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