Oxidative stress and altered lipid homeostasis in the programming of offspring fatty liver by maternal obesity

Abstract

Changes in the maternal nutritional environment during fetal development can influence offspring's metabolic risk in later life. Animal models have demonstrated that offspring of diet-induced obese dams develop metabolic complications, including nonalcoholic fatty liver disease. In this study we investigated the mechanisms in young offspring that lead to the development of nonalcoholic fatty liver disease (NAFLD). Female offspring of C57BL/6J dams fed either a control or obesogenic diet were studied at 8 wk of age. We investigated the roles of oxidative stress and lipid metabolism in contributing to fatty liver in offspring. There were no differences in body weight or adiposity at 8 wk of age; however, offspring of obese dams were hyperinsulinemic. Oxidative damage markers were significantly increased in their livers, with reduced levels of the antioxidant enzyme glutathione peroxidase-1. Mitochondrial complex I and II activities were elevated, while levels of mitochondrial cytochrome c were significantly reduced and glutamate dehydrogenase was significantly increased, suggesting mitochondrial dysfunction. Offspring of obese dams also had significantly greater hepatic lipid content, associated with increased levels of PPARγ and reduced triglyceride lipase. Liver glycogen and protein content were concomitantly reduced in offspring of obese dams. In conclusion, offspring of diet-induced obese dams have disrupted liver metabolism and develop NAFLD prior to any differences in body weight or body composition. Oxidative stress may play a mechanistic role in the progression of fatty liver in these offspring.

Effect of maternal obesity on pregnancy outcomes and long-term metabolic consequences

“…77 Human studies using magnetic resonance imaging have shown that maternal BMI predicts infant intrahepatocellular lipid storage, as seen in animal models, which implies that maternal obesity may predispose the offspring to developing nonalcoholic fatty liver, the hepatic manifestation of metabolic syndrome. 78,79 Furthermore, maternal obesity appears to downregulate fetal myogenesis. Skeletal muscle is the principal site for glucose and fatty acid utilization.…”

The peroxisome proliferator-activated receptors under epigenetic control in placental metabolism and fetal development

“…Changes in gene methylation have been identified to be important in the context of upregulation of genes that control hepatic fatty acid oxidation and gluconeogenesis in energydemanding tissues (i.e., liver, heart muscle; Tables 1 and 3). Whereas recent studies in rodent models of maternal overnutrition identified a sex-specific upregulation of hepatic expression of Pparg (Table 3) (2,24), nutritional effects in animal models of poor nutrition were shown to be mediated through Ppara and the glucocorticoid receptor (Nr3c1, also known as Gr; Table 1 and Fig. 1) (17,87,89,129).…”

Both Hepatic Lipogenesis and Beta-Oxidation are Altered in Offspring of Mothers Fed a High-Fat Diet in the First Two Generations (F1 and F2)

“…A growing body of evidence has associated maternal nutrition with altered offspring metabolism (Alfaradhi et al, 2014;Ornellas et al, 2015). A high fat (HF) fed mothers favors the early onset of obesity and its comorbidities in the offspring even when there is balanced nutrition in their postweaning life (Gregorio et al, 2010).…”