MATERNAL OBESITY PROGRAMS EARLY AGING OF MALE RAT OFFSPRING (F1) LIVER METABOLISM AND TRANSCRIPTOME

Maternal obesity (MO) predisposes F1 offspring to chronic disorders including non-alcoholic fatty liver disease (NAFLD). With aging, the liver undergoes structural and functional changes associated with metabolic impairment. Mechanism(s) whereby MO and/or aging cause NAFLD are unknown. F0 female rats ate control (C) or obesogenic diet (MO) from weaning through lactation. After weaning F1 males ate C diet. At postnatal day (PND) 110 and 650 F1 serum and liver OS measures, liver histology, immunohistochemistry (IHC), and transcriptomics (RNA-seq) were evaluated. Data M ± SE. 110d MO F1 show impaired hepatic lipid function, increased NAFLD and OS markers; liver fat (C110, 2.7 ± 0.8; MO110 11.0 ± 0.7; C650 6.0 ± 0.9; MO650 29.0 ± 2.0 % area stained), lipoperoxidation (C110, 24.4 ± 3.4; MO110 36.1 ± 3.0; C650 35.9 ± 1.6; MO650 50.6 ± 2.2 nMol/mg protein). MO antioxidant enzymes decreased earlier than C F1, exacerbated in MO650 vs. C650. RNA-seq demonstrated differentially expressed genes (DEG) down regulated by age (C 110 vs C 650, 97%) and diet (C110 vs MO110, 95%). All five oxidative phosphorylation complexes showed decrease gene expression in MO F1 110d, e.g. mRNA Nduf10 (C110, 6.2 ± 0.09; MO110 5.6 ± 0.12; C650 5.4 ± 0.30; MO650 5.52 ± 0.18 A.U.), also SIRT-2 mRNA and protein (C110, 15.3 ± 1; MO110 9.8 ± 0.5; C650 12.1 ± 0.5; MO650 9.9 ± 0.5 % of area) were decreased to C650 levels indicating premature aging. We conclude MO programs metabolic dysfunction and down regulation of oxidative phosphorylation genes, especially complex 1 the major site of ROS production, leading to NAFLD accelerating metabolic dysfunction, predisposing F1 to premature aging.