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Cited by 137Birth, Development, and HealthLiver Disease Diagnosis and TreatmentDiet, Metabolism, and Disease

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

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Alfaradhi, Maria Z., Fernandez-Twinn, Denise S., Martin-Gronert, Malgorzata S., Musial, Barbara, Fowden, Abigail, Ozanne, Susan E.·2014·American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
DOI 10.1152/ajpregu.00049.2014PMC PMC4080277
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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.

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Fig. 1. Insulin and oxidative stress markers. A: fasting serum insulin concentration. B: serum 8-hydroxy-2-deoxy guanosine (8-OH-dG) concentration. C: liver 3-nitrotyrosine (3NT) concentration. D: liver 4-hydroxynonenal (4HNE) concentration. E: protein levels of liver tumor necrosis factor-α (TNF-α). Data are presented as means ± SE for control (white bar) and maternal obesity (Mat-Ob) (gray bar) offspring. n = 6–8 per group. *P < 0.05, **P < 0.01.
Fig. 1. Insulin and oxidative stress markers. A: fasting serum insulin concentration. B: serum 8-hydroxy-2-deoxy guanosine (8-OH-dG) concentration. C: liver 3-nitrotyrosine (3NT) concentration. D: liver 4-hydroxynonenal (4HNE) concentration. E: protein levels of liver tumor necrosis factor-α (TNF-α). Data are presented as means ± SE for control (white bar) and maternal obesity (Mat-Ob) (gray bar) offspring. n = 6–8 per group. *P < 0.05, **P < 0.01.CC BY · PubMed Central
Fig. 2. Oxidative homeostasis. A: protein levels of oxidative and nitrosative enzymes. eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; XO, xanthine oxidase; NOX4, NADPH oxidase 4. B: protein levels of antioxidant enzymes. MnSOD, manganese superoxide dismutase; GPx1, glutathione peroxidase-1; GR, glutathione reductase; CuZnSOD, copper/zinc superoxide dismutase; HO1, heme oxygenase-1. C: mitochondrial complex activities. D: protein levels of mitochondrial enzymes. COX4, cytochrome-c oxidase complex IV; Cyt c, cytochrome c; glutamate DH, glutamate dehydrogenase. Data are presented as means ± SE for control (white bar) and Mat-Ob (gray bar) offspring. n = 6–8 per group. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 2. Oxidative homeostasis. A: protein levels of oxidative and nitrosative enzymes. eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; XO, xanthine oxidase; NOX4, NADPH oxidase 4. B: protein levels of antioxidant enzymes. MnSOD, manganese superoxide dismutase; GPx1, glutathione peroxidase-1; GR, glutathione reductase; CuZnSOD, copper/zinc superoxide dismutase; HO1, heme oxygenase-1. C: mitochondrial complex activities. D: protein levels of mitochondrial enzymes. COX4, cytochrome-c oxidase complex IV; Cyt c, cytochrome c; glutamate DH, glutamate dehydrogenase. Data are presented as means ± SE for control (white bar) and Mat-Ob (gray bar) offspring. n = 6–8 per group. *P < 0.05, **P < 0.01, ***P < 0.001.CC BY · PubMed Central
Fig. 3. Liver lipid metabolism. A: protein levels of lipogenic enzymes. ACC, acetyl coA carboxylase; PDH, pyruvate dehydrogenase; PPARγ, peroxisome proliferator activator receptor γ; FAS, fatty acid synthase; SREBP1, sterol regulatory element-binding protein 1. B: protein levels of lipolytic enzymes. PPARα, peroxisome proliferator activator receptor α; LPL, lipoprotein lipase; ATGL, adipose triglyceride lipase; 5-LO, 5-lipoxygenase; CYP4A14, cytochrome P-450 4A14. C: total liver lipid content determined from 100 mg liver tissue. D: representative Oil-red-O (ORO) and hematoxylin-and-eosin (H&E) histology images. Scale bar is 50 μm. E: quantification of lipid droplet staining. Data are presented as means ± SE for control (white bar) and Mat-Ob (gray bar) offspring. n = 6–8 per group; *P < 0.05, ***P < 0.001.
Fig. 3. Liver lipid metabolism. A: protein levels of lipogenic enzymes. ACC, acetyl coA carboxylase; PDH, pyruvate dehydrogenase; PPARγ, peroxisome proliferator activator receptor γ; FAS, fatty acid synthase; SREBP1, sterol regulatory element-binding protein 1. B: protein levels of lipolytic enzymes. PPARα, peroxisome proliferator activator receptor α; LPL, lipoprotein lipase; ATGL, adipose triglyceride lipase; 5-LO, 5-lipoxygenase; CYP4A14, cytochrome P-450 4A14. C: total liver lipid content determined from 100 mg liver tissue. D: representative Oil-red-O (ORO) and hematoxylin-and-eosin (H&E) histology images. Scale bar is 50 μm. E: quantification of lipid droplet staining. Data are presented as means ± SE for control (white bar) and Mat-Ob (gray bar) offspring. n = 6–8 per group; *P < 0.05, ***P < 0.001.CC BY · PubMed Central
Fig. 4. Liver glycogen metabolism. A: liver glycogen content. B: protein levels of total glycogen synthase kinase-3 isoforms and their phosphorylation levels. C: protein levels of gluconeogenic enzymes. PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6 phosphatase. Data are presented as means ± SE for control (white bar) and Mat-Ob (gray bar) offspring. n = 6–8 per group, *P < 0.05.
Fig. 4. Liver glycogen metabolism. A: liver glycogen content. B: protein levels of total glycogen synthase kinase-3 isoforms and their phosphorylation levels. C: protein levels of gluconeogenic enzymes. PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6 phosphatase. Data are presented as means ± SE for control (white bar) and Mat-Ob (gray bar) offspring. n = 6–8 per group, *P < 0.05.CC BY · PubMed Central

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  1. Dandona P, 2001, J Clin Endocrinol Metab, 86, 355
  2. McCurdy CE, 2009, J Clin Invest, 119, 323

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Metadata

Authors
Alfaradhi, M. Z., Fernandez-Twinn, D. S., Martin-Gronert, M. S., Musial, B., Fowden, A., & Ozanne, S. E.
Affiliations
  • University of Cambridge (GB)
  • University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom; and
  • Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
Corresponding author
Alfaradhi, Maria Z.
ORCID
Venue
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
Publisher
American Physiological Society
Published
2014-07-01
Volume
307
Issue
1
Pages
R26-R34
ISSN
  • 0363-6119 (ISSN-L)
  • 1522-1490
DOI
10.1152/ajpregu.00049.2014
PMC
PMC4080277
OpenAlex
W2128764301
Cited by
136
References
42
Citations by year
2026: 4 · 2025: 7 · 2024: 10 · 2023: 13 · 2022: 13 · 2021: 14 · 2020: 13 · 2019: 7 · 2018: 11 · 2017: 10 · 2016: 16 · 2015: 15 · 2014: 3
FWCI
13.80
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • British Heart Foundation (FS/09/029/27902)
  • Biotechnology and Biological Sciences Research Council (BB/F015364/1)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Keywords
non-alcoholic fatty liver disease, maternal obesity, developmental programming, oxidative stress, lipid homeostasis, hyperinsulinemia, glutathione peroxidase 1, mitochondrial dysfunction, PPARγ, hepatic lipase, liver glycogen, obesogenic diet
MeSH terms
Glutathione Peroxidase GPX1, Age Factors, Animals, Animal Nutritional Physiological Phenomena, Body Weight, Fatty Liver, Female, Glutamate Dehydrogenase, Glutathione Peroxidase, Glycogen, Homeostasis, Insulin, Lipase, Liver, Mice, Inbred C57BL, Obesity, Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Risk Factors, Signal Transduction, Oxidative Stress, Prenatal Nutritional Physiological Phenomena, Electron Transport Complex II, Electron Transport Complex I, Cytochromes c, PPAR gamma, Adiposity, Lipid Metabolism, Mice, Non-alcoholic Fatty Liver Disease

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