Abstract
Obesity and metabolic disease present a danger to long-term health outcomes. It has been hypothesized that epigenetic marks established during early life might program individuals and have either beneficial or harmful consequences later in life. In the present study, we examined whether maternal diet alters DNA methylation and whether such modifications persist after an obesogenic postnatal dietary challenge. During gestation and lactation, male Sprague-Dawley rats were exposed to either a high-fat diet (HF; n = 10) or low-fat diet (LF; n = 10). After weaning, all animals were fed a HF diet for an additional nine weeks. There were no differences observed in food intake or body weight between groups. Hepatic DNA methylation was quantified using both methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme sequencing (MRE-seq). Overall, 1419 differentially methylated regions (DMRs) were identified. DMRs tended to be located in CpG shores and were enriched for genes involved in metabolism and cancer. Gene expression was measured for 31 genes in these pathways. Map3k5 and Igf1r were confirmed to be differentially expressed. Finally, we attempted to quantify the functional relevance of intergenic DMRs. Using chromatin contact data, we saw that conserved DMRs were topologically associated with metabolism genes, which were associated with differential expression of Adh5, Enox1, and Pik3c3. We show that although maternal dietary fat is unable to reverse offspring weight gain in response to a postnatal obesogenic diet, early life diet does program the hepatic methylome. Epigenetic alterations occur primarily in metabolic and cancer pathways and are associated with altered gene expression, but it is unclear whether they bear consequence later in life.
Highlights
IntroductionCalorie-dense diets, including those that are high in fat and sucrose, have been shown to blunt insulin sensitivity [1,2], increase the risk for cardiovascular disease [3,4], and increase the incidence of certain types of cancer [5,6]
Obesogenic diets are associated with a host of chronic diseases
An obesogenic postnatal diet only resulted in cardiac hypertrophy and elevated fibrosis if it was preceded by an obesogenic prenatal diet, but not if it was preceded by a prenatal LF diet [9]
Summary
Calorie-dense diets, including those that are high in fat and sucrose, have been shown to blunt insulin sensitivity [1,2], increase the risk for cardiovascular disease [3,4], and increase the incidence of certain types of cancer [5,6]. While consumption of a high-fat (HF) diet is known to produce undesirable outcomes, it has been suggested that maternal diet may play an important role in preventing the negative consequences of poor postnatal diet. Nutrients 2019, 11, 2075 weaning had larger adipocytes, higher fasting glucose and insulin levels, and reduced expression of insulin signaling proteins [7,8]. A maternal low-fat (LF) diet significantly reduced adipocyte size, lowered fasting glucose and insulin, and ameliorated the protein expression changes. An obesogenic postnatal diet only resulted in cardiac hypertrophy and elevated fibrosis if it was preceded by an obesogenic prenatal diet, but not if it was preceded by a prenatal LF diet [9]
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