Maternal Obesity Programs the Premature Aging of Rat Offspring Liver Mitochondrial Electron Transport Chain Genes in a Sex-Dependent Manner

SIMPLE SUMMARY: Developmental programming is now an area of considerable interest throughout the biomedical research community as it is now well accepted that challenges during fetal and early neonatal life program the trajectory of the development and function of multiple systems across the life span. There is now also compelling evidence that developmental programming alters the trajectory of aging, beginning early in life. The present study links mitochondrial function to molecular signaling pathways that regulate life span and to the aging process; it demonstrates the role and importance of mitochondria in the predisposition to developing a fatty liver. The overall message we wish to emphasize is that hepatic aging in offspring caused by maternal obesity in rats involves changes in the mitochondrial function pathways that result in fatty livers. These processes show sexual dimorphism as they occur in males and females at different ages. These findings throw new light on the mechanisms that underlie the well-established sexual dimorphism in aging. We hope this paper will be a stimulus to similar studies on other tissues. ABSTRACT: We investigated whether maternal obesity affects the hepatic mitochondrial electron transport chain (ETC), sirtuins, and antioxidant enzymes in young (110 postnatal days (PND)) and old (650PND) male and female offspring in a sex- and age-related manner. Female Wistar rats ate a control (C) or high-fat (MO) diet from weaning, through pregnancy and lactation. After weaning, the offspring ate the C diet and were euthanized at 110 and 650PND. The livers were collected for RNA-seq and immunohistochemistry. Male offspring livers had more differentially expressed genes (DEGs) down-regulated by both MO and natural aging than females. C-650PND vs. C-110PND and MO-110PND vs. C-110PND comparisons revealed 1477 DEGs in common for males (premature aging by MO) and 35 DEGs for females. Analysis to identify KEGG pathways enriched from genes in common showed changes in 511 and 3 KEGG pathways in the male and female livers, respectively. Mitochondrial function pathways showed ETC-related gene down-regulation. All ETC complexes, sirtuin2, sirtuin3, sod-1, and catalase, exhibited gene down-regulation and decreased protein expression at young and old ages in MO males vs. C males; meanwhile, MO females down-regulated only at 650PND. Conclusions: MO accelerates the age-associated down-regulation of ETC pathway gene expression in male offspring livers, thereby causing sex-dependent oxidative stress, premature aging, and metabolic dysfunction.