Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation

Abstract

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/β-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.

Maternal obesity has sex‐dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring

“…According to one study in non‐human primate programmed by MO, fetal liver pathways altered in response to MO were TCA cycle, proteasome, oxidative phosphorylation, glycolysis signalling pathways together with lipid accumulation; they suggest that as fetuses F1 are on an early trajectory of NAFLD and NASH (Puppala et al . ). Those pathways are also dysregulated in rat liver MO‐F1 in our study.…”

A mother's gift: consequences of unhealthy diet for offspring metabolism

“…In this context, a recent article published in The Journal of Physiology by Puppala et al . () has advanced this research line with non‐human primates, in this case baboons ( Papio hamadryas ). In their study, the authors examined the molecular mechanisms (genetic and epigenetic changes) by which maternal obesity impacts the developing baboon fetal liver resulting in dysregulation of key metabolic pathways that impact lipid metabolism.…”

“…The aim of Puppala et al . was to examine the molecular mechanisms by which a high‐fat maternal diet affects the developing fetal liver. To that end, a group of 32 healthy female baboons of similar age, body dimensions and weight were fed with diets differentiated for the supply of fats and sugars for at least 9 months before pregnancy.…”

“…Puppala et al . () is the first study in which unbiased transcriptome analysis has been used to identify potential miRNA epigenetic regulators of metabolic disruption in livers of non‐human primate fetuses with maternal obesity.…”

“…Although the study of Puppala et al . () has limitations in its ability to show significant changes during early stages of fetal development, it was shown that during the critical time of fetal development, the epigenetic changes could influence gene expression and modulate the offspring's phenotype later, with the liver being one of the main targets for metabolic programming during this development. This result encourages future studies in MO postnatal offspring to determine the extent of this dysregulation on fetal hepatic metabolism.…”