Maternal Obesity Programs Offspring's Predisposition to Non‐Alcoholic Fatty Liver Disease and Steatohepatitis

Abstract

Maternal obesity and unbalanced diets during pregnancy are key factors in determining the risk of obesity in later life. Non‐alcoholic fatty liver disease (NAFLD) is an important co‐morbidity associated with obesity and metabolic dysfunction and a precursor to steatohepatitis (NASH). However, the contributions of gestational and early neonatal influences on development of NAFLD and subsequent NASH remain poorly appreciated. Using a model of controlled overfeeding, we have previously demonstrated that in utero exposure to maternal obesity during pregnancy alone leads to metabolic programming of liver, characterized by metabolic inflexibility. Here we examine the hypothesis that maternal over‐nutrition via in utero exposure to high fat diet induces inflammation and leads to exacerbated hepatic responses to post‐natal high fat diets (HFD) and methionine choline deficient (MCD) diets in the offspring. Female C57BL6/J mice were fed diets with either low (10%) or HFD (45% of calories) for 12 wk starting at 5 wk of age. Dams were mated with males on control diets and provided access to respective diets during pregnancy and lactation. At weaning, offspring were weaned onto control and HFD, creating four groups (CC, CH, HC, HH, denoting maternal and offspring diets, respectively). Offspring of obese mice dams (HH n=7) gained greater body weight and fat mass when fed HFD, compared to offspring from lean dam (CH n=11). Serum cholesterol concentrations were higher in HH compared to CH groups. Global hepatic gene expression and microbial ecology of the cecal contents in offspring was studied using RNAseq and 16S rRNA sequencing. Hepatic expression of Mcp1 and MMP13 gene expression was higher in HH compared to CC and CH indicative of inflammation in response to maternal high fat diet. Analysis of microbial OTUs with Multivariate association with linear models (MaAsLin) and LeFSE showed higher abundance of Firmicutes and lower abundance of Bacteriodetes in HH as well as CH compared to CC. To assess the susceptibility of offspring to NASH, 8 wk old offspring in a separate study were challenged with either control or MCD diets for 4 wk. MCD diet led to significant weight reduction irrespective of maternal nutritional background. Serum ALT was modestly higher in offspring from obese dams (HFD/MCD) relative to lean dam cohorts. Offspring of HF dams showed similar inflammatory changes but greater pro‐fibrogenic alterations following MCD diet. MaAsLin and LeFSE analysis revealed association between serum ALT levels, Coprococcus and MCD treatment. Genome‐scale DNA methylation of livers showed alterations in CpGs associated with cell adhesion, cell communication and development with MCD challenge, including genes in the TGF‐β signaling pathways. Overall, our findings indicate that maternal obesity during gestation and lactation detrimentally alters epigenetic and gut microbiome pathways to favor development of fatty liver disease and its progressive sequelae.Support or Funding InformationSupport USDA CRIS 6206‐51000‐010‐05S