Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats

Abstract

Non-technical summary An excess production of liver glucose is common in patients with diabetes, and animal studies show that female rats who consume a high-fat diet during pregnancy may give birth to offspring who are more likely to develop diabetes in adulthood. However, how this may be occurring remains poorly understood. The present study investigated the effect of a maternal high fat diet on fetal genes in the liver that control the production of glucose, and the potential regulatory mechanisms of these genes. We observed that pups of high fat-fed dams were heavier and had higher blood glucose at the time of delivery than pups of dams fed the control diet. While the high fat-fed dams themselves did not have increased blood glucose, their pups had higher expression of genes to make glucose in addition to elevated blood glucose. Our study demonstrates that exposure to a high fat diet during pregnancy programs the over-production of glucose in livers of offspring, which has the potential to lead to type II diabetes in childhood and adulthood.Abstract In insulin resistance and type II diabetes, there is an elevation of hepatic gluconeogenesis, which contributes to hyperglycaemia. Studies in experimental animals have provided evidence that consumption of high fat (HF) diets by female rats programs the progeny for glucose intolerance in adulthood, but the mechanisms behind the in utero programming remain poorly understood. The present study analysed the effect of a maternal HF diet on fetal gluconeogenic gene expression and potential regulation mechanism related to histone modifications. Dams were fed either a Control (C, 16% kcal fat) or a high-fat (HF, 45% kcal fat) diet throughout gestation. Livers of the offspring were collected on gestational day 21 and analysed to determine the consequences of a maternal HF diet on molecular markers of fetal liver gluconeogenesis. We demonstrated that offspring of HF-fed dams were significantly heavier and had significantly higher blood glucose levels at the time of delivery than offspring of dams fed the C diet. While maternal gluconeogenesis and plasma glucose were not affected by the HF diet, offspring of HF-fed dams had significantly higher mRNA contents of gluconeogenic genes in addition to the elevated plasma glucose. In addition to increased transcription rate, a gestational HF diet resulted in modifications of the Pck1 histone code in livers of offspring. Our results demonstrate that in utero exposure to HF diet has the potential to program the gluconeogenic capacity of offspring through epigenetic modifications, which could potentially lead to excessive glucose production and altered insulin sensitivity in adulthood.

Effect of intrauterine growth retardation on liver and long-term metabolic risk

“…69 Mice offspring of dams with high fat intake during pregnancy show insulin resistance, reduced glucose transporter-2 expression and hepatic steatosis. 70,71 Consistently, in utero exposure to high fat diet programs the expression and epigenetics of hepatic phosphoenolpyruvate carboxykinase gene in offspring rats 72 and affects hepatic energy sensing pathways in a porcine model. 73 Finally, in heterozygous leptin receptor-deficient mice, the exposure to maternal gestational diabetes mellitus induces hepatic insulin resistance in the adult offspring.…”

Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity

“…Recent evidence has emerged from studies on the independent effects of maternal high-fat feeding that support the hypothesis that increased circulating lipids, as opposed to maternal obesity per se, are the mediator of fetal programming (36,43,65). Importantly, gestational exposure to high-fat diets has been associated with epigenetic changes (histone acetylation and methylation) in adipokine genes (43) and genes regulating glucose metabolism (65) in offspring tissues.…”

Epigenetics and Metabolism

“…In accordance with differential expression of Sirt1, Gcn5, Hdac1, and Hdac3, enrichment of histone acetylation, and also histone methylation, was observed at promoters of genes important for lipid metabolism in livers of fetal and 5-week offspring. 206,207 Similar histone lysine modifications were associated with developmentally programmed changes in leptin and adiponectin expression in adipose tissue.…”