Liver Proteome Profile of Growth Restricted and Appropriately Grown Newborn Wistar Rats Associated With Maternal Undernutrition

Abstract

BackgroundFetal growth restriction (FGR) has been associated with adverse perinatal outcomes and epigenetic modifications that impact gene expression leading to permanent changes of fetal metabolic pathways and thereby influence development of disease in childhood and adult life. In this study, we investigated the result of maternal food restriction on liver protein expression in Wistar male newborn pups.Materials & MethodsTen (n = 10) timed pregnant Wistar rats on their 14th day of gestation were randomly assigned to either control (n = 4) or food restricted group (n = 6). The control group had ad libitum access to food. In the food restricted group, maternal diet was limited in a moderate fashion (50%) from day 15 of pregnancy until delivery. All rats delivered spontaneously on day 21 and newborn pups were immediately weighed. Pups born to normally nourished mothers were considered as controls, while pups born to food restricted mothers were subdivided into two groups, based on their birth weight: growth restricted (FGR) and appropriately grown (non-FGR). Rats were euthanized immediately after birth and liver tissues of 11 randomly selected male offspring (FGR n = 4, non-FGR n = 4, control n = 3) were collected and analyzed using quantitative proteomics.ResultsIn total 6,665 proteins were profiled. Of these, 451 and 751 were differentially expressed in FGR and non-FGR vs. control, respectively, whereas 229 proteins were commonly expressed. Bioinformatics analysis of the differentially expressed proteins (DEPs) in FGR vs. control revealed induction of the super-pathway of cholesterol biosynthesis and inhibition of thyroid hormone metabolism, fatty acid beta oxidation and apelin liver signaling pathway. Analysis of DEPs in non-FGR vs. control groups showed inhibition of thyroid hormone metabolism, fatty acid beta oxidation, and apelin liver signaling pathway.ConclusionThis study demonstrates the impact of prenatal food restriction on the proteomic liver profile of FGR and non-FGR offspring underlying the importance of both prenatal adversities and birth weight on liver-dependent postnatal disease.

Intrauterine growth restriction in piglets modulates postnatal immune function and hepatic transcriptional responses independently of energy intake

“…Moreover, in accordance with our pathway analysis indicating an upregulation of transcriptional activity related to beta-oxidation of fatty acids, studies in rats have indicated that IUGR increased hepatic Prkaa2 expression, a subunit of AMP-activated protein kinase (a master regulator of mitochondrial beta-oxidation) ( Shen, Zhu, and Du, 2022 ). Furthermore, proteomic studies in rat hepatic tissues have demonstrated a marked enrichment of pathways related to beta-oxidation ( Sarli et al, 2021 ). Collectively, these different studies indicate a remarkably conserved response across multiple mammalian species, whereby IUGR redirects pyruvate metabolism away from the citric acid cycle and toward gluconeogenesis, as well as promoting the oxidation of fatty acids as an energy source, likely an adaption to nutrient scarcity in the intra-uterine environment.…”

Rodent models in placental research. Implications for fetal origins of adult disease

“…In the liver of growth-restricted male offspring, elevated levels of triglycerides along with increased protein expression levels of lipoprotein lipase (LPL) were explained by an increase in the hepatic expression levels of liver X receptors (LXRs)-α expression that binds to the putative response elements in the LPL promoter regions (Zhu et al, 2016). In the same way, Wistar rats born to dams fed with 50% restricted diet showed induction of cholesterol biosynthesis with higher concentrations of very-low-density lipoprotein (VLDL) and lowdensity lipoprotein (LDL), lipoproteins, and triglycerides (Sarli et al, 2021). Therefore, abnormalities in adipose tissue and liver lead to dyslipidemia with metabolic consequences.…”

A Final Frontier in Environment-Genome Interactions? Integrated, Multi-Omic Approaches to Predictions of Non-Communicable Disease Risk

“…Therefore, a complete picture of cellular activity cannot be determined from the transcriptome alone. Recent studies connect the proteome to immune dysregulation and obesity ( Garrison et al, 2017 ) and traits relevant to the DOHaD hypothesis ( Sarli et al, 2021 ). Moreover, the proteome is known to respond to environmental stimuli ( Koga et al, 2011 ; Calamini and Morimoto, 2012 ) including diet ( Vileigas et al, 2019 ), chemical exposure ( Lee et al, 2018 ) and smoking ( Sinha et al, 2021 ).…”