Alterations in hepatic gene expression and genome‐wide DNA methylation in rat offspring exposed to maternal obesity in utero

Adult offspring from obese (OB) rat dams gain greater body weight and fat mass than controls when fed HFD. At PND21, we examined energy expenditure (EE) (indirect calorimetry), hepatic gene expression (microarrays), and changes in genome‐wide and global DNA methylation (enrichment‐coupled DNA sequencing, Illumina), coupled with specific signaling pathway analysis. Microarray analyses revealed a reprogramming of lipogenic and lipid degradative pathways as shown by increased expression of SREBP‐1 and decreased PPAR‐α/AMPK signaling. Offspring from OB dams had decreased EE (p<0.05) and higher respiratory exchange ratio values (p<0.05) on AIN‐93G or HFD, indicating an impaired capacity to utilize fatty acids (FA). Mitochondrial (mito) protein content of electron transport chain complexes (II, III, and ATPase) was decreased (p<0.03) in OB dam offspring. Hepatic mRNA and mito protein expression of SIRT3, a regulator of mito oxidative capacity and FA oxidation were decreased (p<0.002) in OB dam offspring. Fasting‐induced increases in mRNA and protein expression of PGC‐1α and PPAR‐α were diminished in OB dam offspring. The 3′‐UTR region of PPAR‐α was hypermethylated in offspring of OB dams consistent with impaired FA mobilization. Maternal obesity influences early hepatic gene expression and DNA methylation. Further, it appears that mito dysfunction precedes the development of excessive weight gain in offspring from OB dams. Support NIHR01‐ DK084225