A Maternal High-Fat Diet Represses the Expression of Antioxidant Defense Genes and Induces the Cellular Senescence Pathway in the Liver of Male Offspring Rats

Abstract

Maternal high-fat (HF) diet feeding is associated with increased risk of developing metabolism-related diseases in adult offspring, including chronic liver disease. The present study tested the hypothesis that maternal HF diet leads to a decreased antioxidant defense capacity and causes cellular senescence in liver of adult offspring rats, which might increase risk of developing chronic liver disease. Timed-pregnant Sprague Dawley rats were fed a HF diet (45% of energy from fat) or a control (C) diet (16% of energy from fat) during gestation and lactation. The resulting offspring were fed a C diet after weaning to generate 2 offspring groups: C diet-fed offspring of dams fed C diet (C/C) and C diet-fed offspring of dams fed a HF diet (HF/C). At 12 wk of age, male rats were killed and samples were collected for analysis. Maternal HF diet significantly increased plasma TG and hepatic TBARS concentrations and the size of hepatic lipid droplets in offspring rats. The expression of antioxidant defense genes, such as glutathione peroxidase-1, Cu/Zn superoxide dismutase (Sod1), paraoxonase enzymes (Pon1, Pon2, and Pon3), were significantly lower in the liver of HF/C pups than in C/C pups. The expression of Inhibitor of cyclin dependent Kinase 4a (p16INK4a), a marker of cellular senescence, and cyclooxygenase-2 (Cox2), a proinflammatory marker, was significantly higher in the HF/C offspring group than in the C/C offspring group. Western-blot analysis shows that cyclin D1 and phosphorylated retinoblastoma protein were significantly lower in HF/C offspring than in C/C offspring. The results provide the first evidence to our knowledge that maternal HF diet might alter antioxidant defense capacity and program the p16INK4a-dependent cellular senescence in the liver of adult offspring.

Mitochondrial biogenesis is decreased in skeletal muscle of pig fetuses exposed to maternal high-energy diets

“…Furthermore, mitochondrial dysfunction leads to lipid peroxide accumulation and increased production of ROS (Kim et al, 2008). Previous studies in rodent model systems indicate that a maternal high-fat diet decreases mitochondrial electron transport chain enzymes activities and antioxidant defense capacity in skeletal muscle and liver of offspring (Bruce et al, 2009;Shelley et al, 2009;Zhang et al, 2011). Consistently, decreased activities of antioxidative enzymes (SOD, GPx and CAT) and increased MDA levels were also observed in skeletal muscle of HE fetuses, suggesting the failure of ROS defense system and more, which is probably one of the major determinants of mitochondrial function alterations (Bonnard et al, 2008).…”

“…Mitochondrial dysfunction in skeletal muscle has been associated with metabolic diseases in human and animal models (Pagel-Langenickel et al, 2010). Likewise, decreased oxidative phosphorylation, antioxidative capacity and mitochondrial electron transport chain enzyme activities in the liver and skeletal muscle have been observed in the offspring subjected to maternal overnutrition and diabetes (Bruce et al, 2009;Zhang et al, 2011;Latouche et al, 2014). In mammals, muscle fibers are formed prenatally, and subsequent skeletal muscle development depends largely on muscle fiber hypertrophy (Nissen et al, 2003;Zou et al, 2016).…”

High-fat diet caused widespread epigenomic differences on hepatic methylome in rat

“…Timed-pregnant Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) were fed with either a control (C, 16% of calories from fat) or an HF diet (HF, 45% of calories from fat) purchased from Research Diets [New Brunswick, NJ; diet source and composition were also published by our group before (36)] throughout gestation and lactation. Rats were kept individually in standard polycarbonate cages with ad libitum access to food and drinking water.…”

“…All samples were reverse-transcribed from the same reaction mixture at the same time with a no-RNA template tube as a negative control. To measure the relative mRNA level of target genes, 25 ng of cDNA was analyzed by quantitative real-time PCR and was assessed using the 2ϫ Perfecta SYBR Green master mix with ROX dye (Quanta BioSciences, http://www.vwr.com) by a 7300 real-time PCR system (Applied Biosystems) as previously described (36). Table 1 lists the primer sequences used in the experiment.…”

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition

“…In addition, genetic manipulation shifting NCOR2 binding affinity to its RID2 domain results in premature aging with reduction of mitochondrial function and antioxidant gene expression (Reilly et al ., 2010). NCOR2 may be a potential therapeutic target with maternal high‐fat diet linked to decreased antioxidant enzyme gene expression in offspring with protection through maternal administration of antioxidants (Zhang et al ., 2011). Notch dysregulation via JAG1, a well‐conserved activating ligand of the Notch receptor (Golson et al ., 2009), was demonstrated in the unexposed aging animals compared to 6‐month‐old controls, with an exacerbated effect in our exposed 6‐month‐old groups.…”