Offspring of Mothers Fed a High Fat Diet Display Hepatic Cell Cycle Inhibition and Associated Changes in Gene Expression and DNA Methylation

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.

High-fat diet caused widespread epigenomic differences on hepatic methylome in rat

“…The nutritional regulation on the epigenome during liver development is very limited. HF diets had been shown to mediate DNA methylation at specific CpG sites on the promoter of gene and affected gene expression, thereby leading to physiological alterations (4,7,10,11,18,29). A recent study that applied Illumina's Infinium Bead Array assessed at 27,578 CpG sites associated with 14,475 genes has shown that a short-term feeding of HF diet induced genome-wide DNA methylation change at CpG sites in the skeletal muscle of healthy young men (17).…”

“…Dysregulation of these genes is primarily associated with aberrant hepatic lipid and glucose metabolism, resulting in the development of various types of noncommunicable diseases, including fatty liver disease and obesity. Additionally, alterations of DNA methylation patterns of cell cycle controlled gene Cdkn1a (10) and growth hormone secretagogue receptor (11) were reported in offspring of a maternal HF model, implying the transgenerational epigenetic effects of HF diet. Correlation of DNA methylation and gene expression has been validated in many of these studies, indicating that the HF diet affects gene regulations through alterations of DNA methylation of particular genes.…”

Early nutrition programming of long-term health

“…Epigenetics comprises, among other more technically challenging methods, the investigation of DNA methylation profiles as the primary mark of environmentally mediated changes to gene expression. While the exact role of epigenetic mechanisms in fetal programming of metabolic diseases and body weight regulation remains to be further investigated, a number of animal models have demonstrated a causal relationship between early nutrition and later metabolic phenotype with gene dysregulation mediating such adverse metabolic outcomes (58)(59)(60)(61)(62) . A recently published article reviews the scientific evidence base of the association between the role of epigenetics in the fetal programming of adverse metabolic outcomes concluding that despite a vast amount of epigenomic data generated, the challenge still is to decipher the biological and clinical relevance of these epigenetic changes (63) .…”

Losing the War Against Obesity: The Need for a Developmental Perspective

“…Again, epigenetic processes probably play a role. Experiments in rats show epigenetic changes in the livers of o spring of dams fed a high-fat diet (32). Children of mothers with gestational diabetes mellitus (GDM)-diabetes that appears during pregnancy and then resolves a er pregnancy-have a greater propensity to develop type 2 diabetes as adults.…”