MD/PhD Candidate Indiana University School of Medicine Greenwood, Indiana, United States
Background: Children born to mothers with obesity are at highest risk of developing metabolic diseases, including Non-alcoholic fatty liver disease (NAFLD). Interestingly, sex-differences in NAFLD development in offspring has been shown in several animal models, but molecular pathways and mechanisms underlying the sex-differences, particularly prior to sexual maturation has not been elucidated. Our study's goal is to define the differentially expressed (DE) genes and identify molecular pathways and biological processes altered in offspring exposed to maternal obesity prior to weaning. Objective: We hypothesize that there are transcriptome differences observed in offspring mice born to obese dams on postnatal day 21 prior to weaning and sexual maturation. The DE transcriptome is due to epigenetic changes. Design/Methods: Female dams were fed chow (Con) or western diet (MatOb) for four weeks prior to mating, through pregnancy and the lactating period as a model of maternal obesity. On postnatal day 21 (P21), offspring liver tissue was collected for histology to assess for development of NAFLD and RNA was isolated for RNAseq (n=4/sex/group). DE genes were defined using FDR < 0.05. Pathway analysis was performed using Web-based Gene Set Analysis Toolkit (WEB-GESTALKT). Results: On P21, we found that all offspring of obese dams had increased lipid deposition within hepatocytes relative to offspring of dams fed a chow diet. Notably, females had larger lipid droplets, suggesting differences in the capacity to utilize excess lipids between males and females. However, no inflammation or necrosis was evident. RNAseq revealed sex-differences in DE genes. Compared to same-sex controls, male offspring of obese dams had 291 up- and 395 downregulated genes. Female offspring of obese dams had 1073 up- and 1019 downregulated genes. Several GO biological processes were similarly enriched in both genders, such as steroid metabolic process (male NES -2.3, female NES -1.2, FDR < 0.05). However, biological processes like regulation of ion transmembrane transport (male NES -1.69, female NES 1.81, FDR < 0.05), regulation of membrane potential (male NES NS, female NES 2.42, FDR < 0.05), and synapse organization (male NES NS, female NES 1.82, FDR < 0.05) were differentially enriched in males and females.
Conclusion(s): Offspring exposed to maternal obesity exhibit sex-differences in liver transcriptome prior to weaning and sexual maturation. These data point at specific pathways that may influence the susceptibility to develop metabolic disease in males and females, and future studies will be directed at identifying the molecular mechanisms.
