Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice
Abstract
Background & aims Obesity induced, non-alcoholic fatty liver disease (NAFLD), is now the major cause in affluent countries, of the spectrum of steatosis-to-cirrhosis. Obesity and NAFLD rates in reproductive age women, and adolescents, are rising worldwide. Our hypothesis was that maternal obesity and lactation transmit to the offspring a pre-disposition to dysmetabolism, obesity and NAFLD. Methods Female mice were fed standard or obesogenic chow, before, throughout pregnancy, and during lactation. The critical developmental period was studied by cross-fostering offspring of lean and obese dams. Offspring were then weaned onto standard chow and studied at 3months. Read-outs included markers of metabolic dysfunction, biochemical and histological indicators of NAFLD, induction of liver fibrogenesis, and activation of pro-fibrotic pathways. Mechanisms involved in programming a dysmetabolic and NAFLD phenotype were investigated by assaying breast milk components. Results Offspring of obese dams had a dysmetabolic, insulin resistant and NAFLD phenotype compared to offspring of lean dams. Offspring of lean dams that were suckled by obese dams showed an exaggerated dysmetabolic and NAFLD phenotype, with increased body weight, as well as increased levels of insulin, leptin, aspartate transaminase, interleukin-6, tumour necrosis factor-alpha, liver triglycerides, steatosis, hepatic fibrogenesis, renal norepinephrine, and liver alpha1-D plus beta1-adrenoceptors, indicative of sympathetic nervous system activation. Obese dams also had raised breast milk leptin levels compared to lean dams. Conclusions Maternal obesity programs development of a dysmetabolic and NAFLD phenotype, which is critically dependent on the early postnatal period and possibly involving alteration of hypothalamic appetite nuclei signalling by maternal breast milk and neonatal adipose tissue derived, leptin.
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Maternal obesity induced greater adiposity and obesity in the offspring.
“a number of studies showed that maternal obesity induced greater adiposity and obesity [95,96,97,98] as well as hepatic steatosis [95,96,99] in the offspring.”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [95]
Maternal obesity induced hepatic steatosis in the offspring.
“a number of studies showed that maternal obesity induced greater adiposity and obesity [95,96,97,98] as well as hepatic steatosis [95,96,99] in the offspring.”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [95]
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“The developmental overnutrition hypothesis suggests that maternal hyperglycemia and obesity predispose offspring to obesity and metabolic dysfunction and may have been transferred from the mother through the placenta (34,35), although the underlying mechanism is elusive.”
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“In addition, CON animals reared by HE foster mothers showed clear and consistent signs of liver injury compared to CON animals reared by CON females (Oben et al., 2010).”
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“Oben et al.(75) demonstrated that obese dams had increased circulating leptin concentrations compared with lean dams, and therefore leptin may mediate programmed alterations to appetite regulation.”
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“In animal models, maternal high fat diets [12] and maternal obesity [13, 14] during pregnancy, predisposes the developing offspring to non-alcoholic steatohepatitis and insulin resistance.”
BackgroundEarly‐life influences on obesity: from preconception to adolescence
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“Indeed, two recent rodent studies (6,7) report that the obesogenic effect of maternal high-fat diet occurs specifically during the suckling period.”
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“In agreement with this concept, cross-fostering of the newborn offspring of lean dams with obese dams increased caloric intake at 3 months of age compared to offspring of lean dams that were fostered by a lean dam (Oben et al. 2010).”
InfluentialMouralidarane, A., Soeda, J., Sugden, D., Bocianowska‐Zbrog, A., Carter, R. M., Ray, S., Saraswati, R., Cordero, P., Novelli, M. R., Fusai, G., et al. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.85 · Cited by 55 · see citing works
Self-citationPediatric Non-Alcoholic Fatty Liver Disease: Nutritional Origins and Potential Molecular Mechanisms
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“presents increased body weight and food consumption, along with metabolic complications evidenced by increased insulin and leptin levels in plasma and development of NAFLD in adulthood [27].”
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The Role of Vitamins in the Pathogenesis of Non-alcoholic Fatty Liver Disease
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“PPAR signaling pathway is a key modulator of liver proteome in pups born to vitamin B(12) deficient rats.”
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“Previous studies in preclinical models demonstrate that maternal consumption of an obesogenic diet during pregnancy and lactation can “developmentally program” obesity and NAFLD in offspring (12, 13).”
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“MHF has a steatogenic and fibrogenic effect in liver but does not necessarily cause hepatic lipid accumulation [100,101].”
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BackgroundDevelopmental Programming of Pediatric Nonalcoholic Fatty Liver Disease
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Self-citationMaternal Stress and Placental Vascular Function and Remodeling
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Maternal diet-induced obesity and offspring cardiovascular health
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“This highlights both the potential role of changes in breast milk composition in development of the offspring phenotype and also highlights the negative impact of nutritional mismatch between gestation and lactation.(54) Offspring of a rat model of maternal obesity during pregnancy and lactation showed night-time elev…”
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- Authors
- Oben, J. A., Mouralidarane, A., Samuelsson, A.-M., Matthews, P. J., Morgan, M. L., Mckee, C., Soeda, J., Fernandez-Twinn, D. S., Martin-Gronert, M. S., Ozanne, S. E., Sigala, B., Novelli, M., Poston, L., & Taylor, P. D.
- Affiliations
- St Thomas' Hospital (GB)
- King's College London (GB)
- The Royal Free Hospital (GB)
- University of Cambridge (GB)
- University College London (GB)
- Corresponding author
- Oben, Jude A.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 52
- Issue
- 6
- Pages
- 913-920
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2034714209
- Cited by
- 314
- References
- 0
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 8 · 2023: 28 · 2022: 24 · 2021: 10 · 2020: 21 · 2019: 31 · 2018: 22 · 2017: 20 · 2016: 28 · 2015: 21 · 2014: 27 · 2013: 25 · 2012: 14
- FWCI
- 13.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- British Heart Foundation (FS/10/003/28163, FS/09/029/27902)
- Biotechnology and Biological Sciences Research Council (BB/F015364/1)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- maternal obesity, non-alcoholic fatty liver disease, developmental programming, lactation, cross-fostering, insulin resistance, leptin, breast milk, liver fibrosis, sympathetic nervous system, adrenergic receptors, leptin resistance, dysmetabolism, offspring phenotype, obesogenic diet
- MeSH terms
- Actins, Adipose Tissue, Animals, Collagen, Fatty Liver, Female, Lactation, Mice, Inbred C57BL, Milk, Obesity, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, Gene Expression, Receptors, Adrenergic, alpha-1, Leptin, Collagen Type I, Metabolic Syndrome, Mice
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