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.
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; and mza22@cam.ac.uk.
Maria Z
MZ
Alfaradhi
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; and.
Denise S
DS
Fernandez-Twinn
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; and.
Malgorzata S
MS
Martin-Gronert
Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
Barbara
B
Musial
Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
Abigail
A
Fowden
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; and.
Susan E
SE
Ozanne
D050154:Adiposity; D000367:Age Factors; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001835:Body Weight; D045304:Cytochromes c / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism; D005260:Female; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D039401:Prenatal Nutritional Physiological Phenomena; D012307:Risk Factors; D015398:Signal Transduction; D000094765:Glutathione Peroxidase GPX1
D007328:Insulin; D047495:PPAR gamma; D006003:Glycogen; D045304:Cytochromes c; D005979:Glutathione Peroxidase; D042963:Electron Transport Complex II; D005969:Glutamate Dehydrogenase; D008049:Lipase; D042967:Electron Transport Complex I; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
developmental programming; maternal obesity; metabolism; nonalcoholic fatty liver disease; oxidative stress