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Maternal Western Diet is Associated with Distinct Preclinical Pediatric NAFLD Phenotypes in Juvenile Nonhuman Primate Offspring [Liver RNA-seq]

ABSTRACT: Pediatric nonalcoholic fatty liver disease (NAFLD) has distinct and variable pathology that affects up to 10% of children, yet causation remains unclear. We have shown that maternal Western- style diet (mWSD) compared with chow diet (mCD) consumption in nonhuman primates (NHP) produces hepatic injury and steatosis in fetal offspring. Here, we define the role of mWSD and postweaning WSD (pwWSD) exposures on potential molecular mechanisms linked to NAFLD development in a cohort of 3-year-old (3YO) juvenile NHP offspring exposed to mCD or mWSD followed by CD or WSD after weaning. We used histologic, transcriptomic, and metabolomic analyses to identify hepatic pathways regulating NAFLD. Offspring exposed to mWSD showed increased hepatic periportal collagen deposition but unchanged hepatic triglyceride levels and body weight. mWSD was associated with a down-regulation of gene expression pathways underlying HNF4 activity, antioxidant signaling, mitochondrial biogenesis, and PPAR signaling. In offspring exposed to both mWSD and pwWSD, liver RNA profiles showed up-regulation of pathways promoting fibrosis and ER stress. pwWSD increased acylcarnitines and decreased anti- inflammatory fatty acids, which was more pronounced when coupled with mWSD exposure. Further, mWSD shifted liver metabolites towards decreased purine catabolism in favor of synthesis, suggesting a mitochondrial DNA repair response.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE220102 | GEO | 2022/12/05

REPOSITORIES: GEO

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Project description:Maternal diet is associated with the development of metabolism-related and other non-communicable diseases in offspring. Underlying mechanisms, functional profiles, and molecular markers are only starting to be revealed. Here, we explored the physiological and molecular impact of maternal Western-style diet on the liver of male and female offspring. C57BL/6 dams were exposed to either a low fat/low cholesterol diet (LFD) or a Western-style high fat/high cholesterol diet (WSD) for six weeks before mating, as well as during gestation and lactation. Dams and offspring were sacrificed at postnatal day 14, and body, liver, and blood parameters were assessed. The impact of maternal WSD on the pups' liver gene expression was characterised by whole-transcriptome microarray analysis. Exclusively male offspring had significantly higher body weight upon maternal WSD. In offspring of both sexes of WSD dams, liver and blood parameters, as well as hepatic gene expression profiles were changed. In total, 686 and 604 genes were differentially expressed in liver (pM-bM-^IM-$0.01) of males and females, respectively. Only 10% of these significantly changed genes overlapped in both sexes. In males, in particular alterations of gene expression with respect to developmental functions and processes were observed, such as Wnt/beta-catenin signalling. In females, mainly genes important for lipid metabolism, including cholesterol synthesis, were changed. We conclude that maternal WSD affects physiological parameters and induces substantial changes in the molecular profile of the liver in two-week-old pups. Remarkably, the observed biological responses of the offspring reveal pronounced sex-specificity. C57BL/6 dams were exposed to either a low fat/low cholesterol diet (LFD) or a Western-style high fat/high cholesterol diet (WSD) as six weeks pre-treatment before mating, as well as during gestation and lactation. Offspring were sacrificed at postnatal week two, livers were removed and RNA samples were subjected to gene expression profiling.

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Maternal Western Diet is Associated with Distinct Preclinical Pediatric NAFLD Phenotypes in Juvenile Nonhuman Primate Offspring [Liver RNA-seq]

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