Abstract

The association between an adverse early life environment and increased susceptibility to later-life metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease is described by the developmental origins of health and disease hypothesis. Employing a rat model of maternal high fat (MHF) nutrition, we recently reported that offspring born to MHF mothers are small at birth and develop a postnatal phenotype that closely resembles that of the human metabolic syndrome. Livers of offspring born to MHF mothers also display a fatty phenotype reflecting hepatic steatosis and characteristics of non-alcoholic fatty liver disease. In the present study we hypothesised that a MHF diet leads to altered regulation of liver development in offspring; a derangement that may be detectable during early postnatal life. Livers were collected at postnatal days 2 (P2) and 27 (P27) from male offspring of control and MHF mothers (n = 8 per group). Cell cycle dynamics, measured by flow cytometry, revealed significant G0/G1 arrest in the livers of P2 offspring born to MHF mothers, associated with an increased expression of the hepatic cell cycle inhibitor Cdkn1a. In P2 livers, Cdkn1a was hypomethylated at specific CpG dinucleotides and first exon in offspring of MHF mothers and was shown to correlate with a demonstrable increase in mRNA expression levels. These modifications at P2 preceded observable reductions in liver weight and liver∶brain weight ratio at P27, but there were no persistent changes in cell cycle dynamics or DNA methylation in MHF offspring at this time. Since Cdkn1a up-regulation has been associated with hepatocyte growth in pathologic states, our data may be suggestive of early hepatic dysfunction in neonates born to high fat fed mothers. It is likely that these offspring are predisposed to long-term hepatic dysfunction.

Highlights

  • Epidemiological studies, large-scale clinical cohorts, and experimental animal models have shown that hormonal, metabolic and nutritional disturbances during critical periods of early development can significantly impact the propensity to develop adverse health outcomes in later life

  • To determine whether differences exist in cell cycle dynamics within the liver of rats born to maternal high fat (MHF) versus CONT offspring during the first week of postnatal life, we fluorescently labelled the DNA of dissociated liver cells from postnatal day 2 (P2) rats, and measured DNA content by flow cytometric analysis

  • No differences in cell cycle dynamics were observed between CONT and MHF offspring in postnatal day 27 (P27) livers, with the majority of cells appearing in a quiescent (G0/ G1) phase irrespective of maternal diet (Figure 1b)

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Summary

Introduction

Epidemiological studies, large-scale clinical cohorts, and experimental animal models have shown that hormonal, metabolic and nutritional disturbances during critical periods of early development can significantly impact the propensity to develop adverse health outcomes in later life (for a review see ref [1]). In this study we sought to determine if a MHF diet during pregnancy and lactation leads to detectable phenotypic changes in the liver of offspring in the early postnatal developmental period and if so, by what mechanism. We report novel observations that MHF diet during pregnancy and lactation leads to epigenetic modifications (DNA methylation) in the liver of offspring during early postnatal life that are associated with the compromised regulation of cell cycle-related genes. These changes were associated with corresponding alterations in cell cycle dynamics, and with overall reduced liver size at a later timepoint. We propose that these changes may at least in part explain the increased risk of metabolic dysfunction observed in these offspring as adults

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