Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 596, Issue 23, Pages 5823-5837Publisher
WILEY
DOI: 10.1113/JP275422
Keywords
maternal obesity; fetal liver; high fat/sugar diet; gene expression; microRNA integration; biological pathways; lipid metabolism
Categories
Funding
- NIH [R24 5R24OD010916]
- Office of Research Infrastructure Programs (ORIP), NIH [P51 OD011133]
- ORIP [C06 RR14578, C06 RR15456, C06 RR013556, C06 RR017515]
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Maternal obesity (MO) increases offspring cardiometabolic disease risk. Altered fetal liver development in response to the challenge of MO has metabolic consequences underlying adverse offspring life-course health outcomes. Little is known about the molecular pathways and potential epigenetic changes regulating primate fetal liver responses to MO. We hypothesized that MO would induce fetal baboon liver epigenetic changes resulting in dysregulation of key metabolic pathways that impact lipid metabolism. MO was induced prior to pregnancy by a high-fat, high-fructose diet. Unbiased gene and microRNA (small RNA Seq) abundance analyses were performed on fetal baboon livers at 0.9 gestation and subjected to pathway analyses to identify fetal liver molecular responses to MO. Fetal baboon liver lipid and glycogen content were quantified by the Computer Assisted Stereology Toolbox. In response to MO, fetal livers revealed dysregulation of TCA cycle, proteasome, oxidative phosphorylation, glycolysis and Wnt/beta-catenin signalling pathways together with marked lipid accumulation supporting our hypothesis that multiple pathway dysregulation detrimentally impacts lipid management. This is the first study of MO programming of the non-human primate fetal liver using unbiased transcriptome analysis to detect changes in hepatic gene expression levels and identify potential microRNA epigenetic regulators of metabolic disruption.
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