Expression of epigenetic machinery genes is sensitive to maternal obesity and weight loss in relation to fetal growth in mice

Abstract

BackgroundMaternal obesity impacts fetal growth and pregnancy outcomes. To counteract the deleterious effects of obesity on fertility and pregnancy issue, preconceptional weight loss is recommended to obese women. Whether this weight loss is beneficial/detrimental for offspring remains poorly explored. Epigenetic mechanisms could be affected by maternal weight changes, perturbing expression of key developmental genes in the placenta or fetus. Our aim was to investigate the effects of chronic maternal obesity on feto-placental growth along with the underlying epigenetic mechanisms. We also tested whether preconceptional weight loss could alleviate these effects.ResultsFemale mice were fed either a control diet (CTRL group), a high-fat diet (obese (OB) group), or a high-fat diet switched to a control diet 2 months before conception (weight loss (WL) group). At mating, OB females presented an obese phenotype while WL females normalized metabolic parameters. At embryonic day 18.5 (E18.5), fetuses from OB females presented fetal growth restriction (FGR; −13 %) and 28 % of the fetuses were small for gestational age (SGA). Fetuses from WL females normalized this phenotype. The expression of 60 epigenetic machinery genes and 32 metabolic genes was measured in the fetal liver, placental labyrinth, and junctional zone. We revealed 23 genes altered by maternal weight trajectories in at least one of three tissues. The fetal liver and placental labyrinth were more responsive to maternal obesity than junctional zone. One third (18/60) of the epigenetic machinery genes were differentially expressed between at least two maternal groups. Interestingly, genes involved in the histone acetylation pathway were particularly altered (13/18). In OB group, lysine acetyltransferases and Bromodomain-containing protein 2 were upregulated, while most histone deacetylases were downregulated. In WL group, the expression of only a subset of these genes was normalized.ConclusionsThis study highlights the high sensitivity of the epigenetic machinery gene expression, and particularly the histone acetylation pathway, to maternal obesity. These obesity-induced transcriptional changes could alter the placental and the hepatic epigenome, leading to FGR. Preconceptional weight loss appears beneficial to fetal growth, but some effects of previous obesity were retained in offspring phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0188-3) contains supplementary material, which is available to authorized users.

Impact of maternal obesity on placental transcriptome and morphology associated with fetal growth restriction in mice

“…It has been shown that placentae from high fat diet-fed obese mouse dams exhibit altered expression of epigenetic machinery genes at term, which could alter the placental epigenome and lead to FGR [19]. High fat diet-induced obesity has also been found to alter the transcriptome of placenta progenitor cells at early stages of development and is associated with later changes in placental function resulting in FGR [17].…”

“…It is recognized that the impact of stressors on placental function and offspring health is closely linked to the stage of tissue development, the type of insult and the sex of the conceptus [21]. Thus, the aim of this study was to identify global changes in the placental transcriptome and related pathways in response to maternal obesity near term at embryonic day (E) 19. Furthermore, we investigated whether the significant transcriptional alterations detected in obese placentae were manifested earlier, i.e., in midgestation (E13), and if these alterations translated into a structural phenotype in male and female placentae.…”

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

“…In another study, it was revealed that the level of H3K9 (and to a lesser extent H3K14) acetylation at TNF-α and COX-2 promoters in monocytes is significantly augmented in diabetic patients (75). Similarly, in the context of epigenetic machineryrelated gene expression, lysine acetyltransferases (human HATs) and Bromodomain-containing protein 2 expressions were found to be elevated (in contrast to the decreased expression of most HDACs) in mice fetal liver and placental labyrinth tissues of fetuses affected by maternal obesity (76). Likewise, Dorneles et al demonstrated that hyperacetylation of H4, accompanied by a decrease in HDAC2 activity, was observed in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) of obese males after strenuous exercise (77).…”

The impact of maternal obesity in pregnancy on placental glucocorticoid and macronutrient transport and metabolism

“…A murine model was used to evaluate the impact of maternal obesity and pre-conception weight loss on the expression of epigenetic genes in two distinct placental zones: the placental labyrinth, known as the fetal placenta in humans, and the junctional zone, referred to as the basal plate or implantation site in humans [102,103]. For four months prior to conception, female mice were fed a control diet, a high fat diet, or a weight loss diet (high fat for two months followed by control diet for two months).…”