Primate fetal hepatic responses to maternal obesity

Epigenetic signalling pathways and lipid accumulation

Sobha Puppala, Cun Li, Jeremy P. Glenn, Romil Saxena, Samer Gawrieh, Amy Quinn, Jennifer Palarczyk, Edward J. Dick, Peter W. Nathanielsz, Laura A. Cox

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Key points: Maternal obesity (MO) and exposure to a high-fat, high-simple-carbohydrate diet during pregnancy predisposes offspring to obesity, metabolic and cardiovascular disorders in later life. Underlying molecular pathways and potential epigenetic factors that are dysregulated in MO were identified using unbiased transcriptomic methods. There was increased lipid accumulation and severe steatosis in the MO baboon fetal liver suggesting that these offspring are on an early trajectory of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. 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.

Original languageEnglish (US)
JournalJournal of Physiology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Epigenomics
Primates
Obesity
Mothers
Lipids
Liver
Papio
MicroRNAs
Pregnancy
Maternal Exposure
Catenins
Liver Glycogen
Wnt Signaling Pathway
Oxidative Phosphorylation
High Fat Diet
Gene Expression Profiling
Glycolysis
Proteasome Endopeptidase Complex
Fatty Liver
Fetal Development

Keywords

  • Biological pathways
  • Fetal liver
  • Gene expression
  • High fat/sugar diet
  • Lipid metabolism
  • Maternal obesity
  • MicroRNA integration

ASJC Scopus subject areas

  • Physiology

Cite this

Primate fetal hepatic responses to maternal obesity : Epigenetic signalling pathways and lipid accumulation. / Puppala, Sobha; Li, Cun; Glenn, Jeremy P.; Saxena, Romil; Gawrieh, Samer; Quinn, Amy; Palarczyk, Jennifer; Dick, Edward J.; Nathanielsz, Peter W.; Cox, Laura A.

In: Journal of Physiology, 01.01.2018.

Research output: Contribution to journalArticle

Puppala, Sobha ; Li, Cun ; Glenn, Jeremy P. ; Saxena, Romil ; Gawrieh, Samer ; Quinn, Amy ; Palarczyk, Jennifer ; Dick, Edward J. ; Nathanielsz, Peter W. ; Cox, Laura A. / Primate fetal hepatic responses to maternal obesity : Epigenetic signalling pathways and lipid accumulation. In: Journal of Physiology. 2018.
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abstract = "Key points: Maternal obesity (MO) and exposure to a high-fat, high-simple-carbohydrate diet during pregnancy predisposes offspring to obesity, metabolic and cardiovascular disorders in later life. Underlying molecular pathways and potential epigenetic factors that are dysregulated in MO were identified using unbiased transcriptomic methods. There was increased lipid accumulation and severe steatosis in the MO baboon fetal liver suggesting that these offspring are on an early trajectory of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. 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.",
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