Impact of Maternal Obesity on Liver Disease in the Offspring: A Comprehensive Transcriptomic Analysis and Confirmation of Results in a Murine Model

Abstract

The global obesity epidemic particularly affects women of reproductive age. Offspring of obese mothers suffer from an increased risk of liver disease but the molecular mechanisms involved remain unknown. We performed an integrative genomic analysis of datasets that investigated the impact of maternal obesity on the hepatic gene expression profile of the offspring in mice. Furthermore, we developed a murine model of maternal obesity and studied the development of liver disease and the gene expression profile of the top dysregulated genes by quantitative real-time polymerase chain reaction (qPCR). Our data are available for interactive exploration on our companion webpage. We identified five publicly available datasets relevant to our research question. Pathways involved in metabolism, the innate immune system, the clotting cascade, and the cell cycle were consistently dysregulated in the offspring of obese mothers. Concerning genes involved in the development of liver disease, Egfr, Vegfb, Wnt2, Pparg and six other genes were dysregulated in multiple independent datasets. In our own model, we observed a higher tendency towards the development of non-alcoholic liver disease (60 vs. 20%) and higher levels of alanine aminotransferase (41.0 vs. 12.5 IU/l, p = 0.008) in female offspring of obese mothers. Male offspring presented higher levels of liver fibrosis (2.4 vs. 0.6% relative surface area, p = 0.045). In a qPCR gene expression analysis of our own samples, we found Fgf21, Pparg, Ppard, and Casp6 to be dysregulated by maternal obesity. Maternal obesity represents a looming threat to the liver health of future generations. Our comprehensive transcriptomic analysis will help to better understand the mechanisms of the development of liver disease in the offspring of obese mothers and can give rise to further explorations.

Severe gestational diabetes mellitus in lean dams is associated with low IL-1α levels and affects the growth of the juvenile mouse offspring

“…The maternal HFD-induced dysmetabolic liver phenotype demonstrates sex differences. Female offspring are prone to liver steatosis and nonalcoholic fatty liver disease; males rather develop liver fibrosis and manifest nonalcoholic steatohepatitis 52 . The higher TAG accumulation in the livers of our female vs. male FFD and GDM offspring mirrors this observation.…”

The Endocrine–Metabolic Axis Regulation in Offspring Exposed to Maternal Obesity—Cause or Consequence in Metabolic Disease Programming?

“…Although no alterations in cord blood Fetuin-A levels were observed, insulin-like growth factor (IGF)-1 and IGF-2 were significantly increased in GDM [102]. Circulating levels of Fibroblast Growth Factor (FGF) 21, a regulator of the systemic lipid metabolism, are increased in NAFLD [103] and GDM offspring during adolescence [104], and it was described that FGF21 gene expression was dysregulated in murine offspring of MO [105].…”

The Role of Acsl1 and Aldh2 in the Increased Risk for Liver Cancer in Offspring of Obese Mothers

“…We recently analyzed the impact of maternal obesity on the gene expression profiles in the offspring ( 9 ). We compiled 11 previously published datasets that compared the gene expression in offspring from obese and non-obese parents.…”