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

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.

Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart.

Low birth weight and accelerated postnatal growth lead to increased risk of cardiovascular disease. We reported previously that rats exposed to a low-protein diet in utero and postnatal catch-up growth (recuperated) develop metabolic dysfunction and have reduced life span. Here we explored the hypothesis that cardiac oxidative and nitrosative stress leading to DNA damage and accelerated cellular aging could contribute to these phenotypes. Recuperated animals had a low birth weight (P<0.001) but caught up in weight to controls during lactation. At weaning, recuperated cardiac tissue had increased (P<0.05) protein nitrotyrosination and DNA single-stranded breaks. This condition was preceded by increased expression of DNA damage repair molecules 8-oxoguanine-DNA-glycosylase-1, nei-endonuclease-VIII-like, X-ray-repair-complementing-defective-repair-1, and Nthl endonuclease III-like-1 on d 3. These differences were maintained on d 22 and became more pronounced in the case of 8-oxoguanine-DNA-glycosylase-1 and nei-endonuclease-VIII-like. This was accompanied by increases in xanthine oxidase (P<0.001) and NADPH oxidase (P<0.05), major sources of reactive oxygen species (ROS). The detrimental effects of increased ROS in recuperated offspring may be exaggerated at 22 d by reductions (P<0.001) in the antioxidant enzymes peroxiredoxin-3 and CuZn-superoxide-dismutase. We conclude that poor fetal nutrition followed by accelerated postnatal growth results in increased cardiac nitrosative and oxidative-stress and DNA damage, which could contribute to age-associated disease risk.

Exercise rescues obese mothers' insulin sensitivity, placental hypoxia and male offspring insulin sensitivity.

The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring.

Maternal Obesity in Pregnancy Developmentally Programs Adipose Tissue Inflammation in Young, Lean Male Mice Offspring.

Obesity during pregnancy has a long-term effect on the health of the offspring including risk of developing the metabolic syndrome. Using a mouse model of maternal diet-induced obesity, we employed a genome-wide approach to investigate the microRNA (miRNA) and miRNA transcription profile in adipose tissue to understand mechanisms through which this occurs. Male offspring of diet-induced obese mothers, fed a control diet from weaning, showed no differences in body weight or adiposity at 8 weeks of age. However, offspring from the obese dams had up-regulated cytokine (Tnfα; P < .05) and chemokine (Ccl2 and Ccl7; P < .05) signaling in their adipose tissue. This was accompanied by reduced expression of miR-706, which we showed can directly regulate translation of the inflammatory proteins IL-33 (41% up-regulated; P < .05) and calcium/calmodulin-dependent protein kinase 1D (30% up-regulated; P < .01). We conclude that exposure to obesity during development primes an inflammatory environment in adipose tissue that is independent of offspring adiposity. Programming of adipose tissue miRNAs that regulate expression of inflammatory signaling molecules may be a contributing mechanism.

Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms.

We determined the effects of maternal diet-induced obesity on offspring adipose tissue insulin signalling and miRNA expression in the aetiology of insulin resistance in later life. Although body composition and glucose tolerance of 8-week-old male offspring of obese dams were not dysregulated, serum insulin was significantly (p<0.05) elevated. Key insulin signalling proteins in adipose tissue were down-regulated, including the insulin receptor, catalytic (p110ß) and regulatory (p85α) subunits of PI3K as well as AKT1 and 2 (all p<0.05). The largest reduction observed was in IRS-1 protein (p<0.001), which was regulated post-transcriptionally. Concurrently, miR-126, which targets IRS-1, was up-regulated (p<0.05). These two features were maintained in isolated primary pre-adipocytes and differentiated adipocytes in-vitro. We have therefore established that maternal diet-induced obesity programs adipose tissue insulin resistance. We hypothesise that maintenance of the phenotype in-vitro strongly suggests that this mechanism is cell autonomous and may drive insulin resistance in later life.

Developmental programming in response to maternal overnutrition.

Metabolic disorders have seen an increased prevalence in recent years in developed as well as developing countries. While it is clear lifestyle choices and habits have contributed to this epidemic, mounting evidence suggests the nutritional milieu during critical stages of development in early life can "program" individuals to develop the metabolic syndrome later in life. Extensive epidemiological data presents an association between maternal obesity and nutrition during pregnancy and offspring obesity, and a number of animal models have been established in order to uncover the underlying mechanisms contributing to the programming of physiological systems. It is hard to distinguish the causal factors due to the complex nature of the maternal-fetal relationship; however, in order to develop adequate prevention strategies it is vital to identify which maternal factor(s) - be it the diet, diet-induced obesity or weight gain - and at which time during early development instigate the programmed phenotype. Curtailing the onset of obesity at this early stage in life presents a promising avenue through which to stem the growing epidemic of obesity.