Maternal Western-Style High Fat Diet Induces Sex-Specific Physiological and Molecular Changes in Two-Week-Old Mouse Offspring

Abstract

Maternal diet is associated with the development of metabolism-related and other non-communicable diseases in offspring. Underlying mechanisms, functional profiles, and molecular markers are only starting to be revealed. Here, we explored the physiological and molecular impact of maternal Western-style diet on the liver of male and female offspring. C57BL/6 dams were exposed to either a low fat/low cholesterol diet (LFD) or a Western-style high fat/high cholesterol diet (WSD) for six weeks before mating, as well as during gestation and lactation. Dams and offspring were sacrificed at postnatal day 14, and body, liver, and blood parameters were assessed. The impact of maternal WSD on the pups’ liver gene expression was characterised by whole-transcriptome microarray analysis. Exclusively male offspring had significantly higher body weight upon maternal WSD. In offspring of both sexes of WSD dams, liver and blood parameters, as well as hepatic gene expression profiles were changed. In total, 686 and 604 genes were differentially expressed in liver (p≤0.01) of males and females, respectively. Only 10% of these significantly changed genes overlapped in both sexes. In males, in particular alterations of gene expression with respect to developmental functions and processes were observed, such as Wnt/beta-catenin signalling. In females, mainly genes important for lipid metabolism, including cholesterol synthesis, were changed. We conclude that maternal WSD affects physiological parameters and induces substantial changes in the molecular profile of the liver in two-week-old pups. Remarkably, the observed biological responses of the offspring reveal pronounced sex-specificity.

Effects of Maternal Obesity on Fetal Programming: Molecular Approaches

“…RNA can be extracted from fluids and tissues of interest to investigate the effects of maternal obesity on fetal gene expression. A variety of fetal and offspring transcriptomes have been studied to help elucidate programming effects of maternal obesity, including the amniotic fluid (Edlow et al 2014), umbilical cord (Thakali et al 2014), liver (Shankar et al 2010; Mischke et al 2013), brain (Stachowiak et al 2013a), and white adipose tissue transcriptomes (Borengasser et al 2013). Transcriptomic analysis has even been performed on the obese maternal uterus and on the blastocyst in the setting of maternal obesity (Shankar et al 2011).…”

“…Whole-genome microarray has been the most commonly used technique to examine the global RNA expression profile. Separate arrays exist for genomes from humans (Hui et al 2013; Edlow et al 2014), mice (Mischke et al 2013), and rats (Shankar et al 2011; Borengasser et al 2013). Functional analysis of the fetal transcriptome via bioinformatics resources such as gene set enrichment analysis (GSEA), database for annotation, visualization and integrated discovery (DAVID), and ingenuity pathways analysis (IPA), and others can highlight particular pathways, biological functions, or physiological systems that are dysregulated in a condition of interest, such as maternal obesity.…”

“…Transcriptomic analysis of human amniotic fluid in the second trimester suggested a proestrogenic, proinflammatory milieu for the developing fetus, with up-regulation of antiapoptotic genes and genes implicated in response to oxidative stress (Edlow et al 2014). Transcriptomic analysis has also been used to evaluate the effect of maternal obesity on fetal brain (Stachowiak et al 2013a) and offspring liver development (Mischke et al 2013), with both organs demonstrating significant changes in gene expression in fetal and pup mice exposed to an obesogenic intrauterine environment.…”

“…Transcriptomic profiling of pup livers exposed to maternal Western-style diet in utero found significant changes in hepatic gene expression profiles compared with controls, but also a striking sexual dimorphism. Males showed alterations of genes related to developmental signaling (such as Wnt/beta-catenin signaling), whereas females showed altered expression of genes related to cholesterol synthesis and lipid metabolism (Mischke et al 2013). …”

“…RT-qPCR, quantitative reverse transcription PCR. (Data for the figure from the following references: 1 Mischke et al 2013; 2 Bruce et al 2009; 3 Vucetic et al 2010; 4 Aagaard-Tillery et al 2008; 5 Suter et al 2011; 6 Borengasser et al 2014; 7 Zhang et al 2009; 8 Benatti et al 2014; 9 Maloyan et al 2013; 10 Elahi and Matata 2014; 11 Yan et al 2013; 12 Borengasser et al 2013; 13 Masuyama and Hiramatsu 2012; 14 Ma et al 2014; 15 Myles et al 2013; 16 Ng et al 2014; 17 Cerf et al 2006; 18 Cerf et al 2009; 19 Jones et al 2009; 20 Zhu et al 2010; 21 Shankar et al 2011; 22 Stachowiak et al 2013b; 23 Moraes et al 2009; 24 Vucetic et al 2010; 25 Franco et al 2012; 26 Suter et al 2012. )…”