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.
Highlights
THE PREVALENCE OF METABOLIC disorders has increased dramatically in the last few decades, in developed and developing countries
Given the accumulating evidence of the importance of de novo lipogenesis in contributing to hepatic lipid deposition and the implications of oxidative stress in the onset of insulin resistance and hepatic steatosis in animal models, we investigated these mechanisms in contributing to nonalcoholic fatty liver disease (NAFLD) onset in our nutritional programming model
It is evident that maternal obesity during pregnancy increases the risk of metabolic diseases in the offspring, including impaired glucose tolerance, insulin resistance, obesity, and NAFLD
Summary
THE PREVALENCE OF METABOLIC disorders has increased dramatically in the last few decades, in developed and developing countries. The development of obesity often results in the onset of further metabolic complications, including insulin resistance and cardiovascular disease, together termed the metabolic syndrome. Features of metabolic syndrome in adult offspring, including NAFLD, have been observed in several animal models of maternal diet-induced obesity [4, 23, 28]. As obesity is a strong predictor of insulin resistance, it confounds the investigation of underlying mechanisms. Oxidative stress has been suggested as a possible trigger for the onset of both insulin resistance and hepatic steatosis [8, 29]. We aimed to investigate the mechanisms underlying the onset of NAFLD in the offspring of dietinduced obese mice. By 3 mo of age, body weights have already diverged with offspring of obese dams being heavier and fatter than controls, confounding the investigation of underlying mechanisms
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