A low protein diet during pregnancy provokes a lasting shift of hepatic expression of genes related to cell cycle throughout ontogenesis in a porcine model

Abstract

BackgroundIn rodent models and in humans the impact of gestational diets on the offspring's phenotype was shown experimentally and epidemiologically. Adverse environmental conditions during fetal development provoke an intrauterine adaptive response termed 'fetal programming', which may lead to both persistently biased responsiveness to extrinsic factors and permanent consequences for the organismal phenotype. This leads to the hypothesis that the offspring's transcriptome exhibits short-term and long-term changes, depending on the maternal diet. In order to contribute to a comprehensive inventory of genes and functional networks that are targets of nutritional programming initiated during fetal life, we applied whole-genome microarrays for expression profiling in a longitudinal experimental design covering prenatal, perinatal, juvenile, and adult ontogenetic stages in a porcine model. Pregnant sows were fed either a gestational low protein diet (LP, 6% CP) or an adequate protein diet (AP, 12% CP). All offspring was nursed by foster sows receiving standard diets. After weaning, all offspring was fed standard diets ad libitum.ResultsAnalyses of the hepatic gene expression of the offspring at prenatal (94 dies post conceptionem, dpc) and postnatal stages (1, 28, 188 dies post natum, dpn) included comparisons between dietary groups within stages as well as comparisons between ontogenetic stages within diets to separate diet-specific transcriptional changes and maturation processes. We observed differential expression of genes related to lipid metabolism (e.g. Fatty acid metabolism, Biosynthesis of steroids, Synthesis and degradation of ketone bodies, FA elongation in mitochondria, Bile acid synthesis) and cell cycle regulation (e.g. Mitotic roles of PLK, G1/S checkpoint regulation, G2/M DNA damage checkpoint regulation). Notably, at stage 1 dpn no regulation of a distinct pathway was found in LP offspring.ConclusionsThe transcriptomic modulations point to persistent functional demand on the liver towards cell proliferation in the LP group but not in the AP group at identical nutritional conditions during postnatal life due to divergent 'programming' of the genome. Together with the observation that the offspring of both groups did not differ in body weight but in body composition and fat content, the data indicate that the activity of various genes led to diverse partitioning of nutrients among peripheral and visceral organs and tissues.

Transcriptional response of skeletal muscle to a low-protein gestation diet in porcine offspring accumulates in growth- and cell cycle-regulating pathways

“…However, neither body weight at weaning nor body weight at 188 dpn differed significantly between offspring of the LP and the AP group, whereas visceral and subcutaneous fat content remained higher in LP than in AP during postnatal life (33)(34)(35). We have previously demonstrated that, depending on the gestational diet, the expression profile of the liver, the central metabolic organ, was affected at both prenatal and postnatal stages; specifically, an altered hepatic expression of genes related to cell cycle and cell maintenance as well as lipid, ketone body, and amino acid metabolism was observed (28). Here, we focus on muscle tissue, representing the largest peripheral consumer of energy and nutrients, contributing to the species-typical shape of the body, and being a main agricultural product for human consumption.…”

“…The possible molecular mechanism explaining the intrauterine adaptive response to adverse environmental changes is termed "fetal programming." Increasing evidence indicates that dietary protein intake below requirement throughout gestation is associated with alterations in gene expression in a species-, tissue-, and stage-specific manner (12,21,28,42). To gain knowledge about transcriptional mechanisms underlying the adaptive response to inadequate nutritional supply, we applied whole-genome microarrays for expression profiling in a longitudinal experimental design.…”

Maternal high-protein diet during pregnancy, but not during suckling, induced altered expression of an increasing number of hepatic genes in adult mouse offspring

“…Only limited protein supply but not protein excess in the pregnancy diet impaired myogenesis, persistently restricting muscle growth potential, and favors higher body fatness during infancy [19]. On the molecular level, maternal LP diet clearly affected offspring hepatic genes involved in lipid metabolism, but also those involved in cell cycle regulation were changed compared to controls [20,21]. Exposure to a maternal HP diet during pregnancy, however, seems to preferentially change hepatic gene expression of energy-sensing pathways in the offspring [22].…”

High‐ and low‐protein gestation diets do not provoke common transcriptional responses representing universal target‐pathways in muscle and liver of porcine progeny

“…) and pigs (Oster et al . , , Theil et al . ) demonstrate that prenatal environmental conditions alter gene expression via unknown diet‐specific mechanisms.…”

“…Previous analyses focused on the transcriptional response to diet at different ontogenetic stages in either skeletal muscle or liver tissue (Oster et al . , ,b,c). Here, we conducted a summative analysis of the complete three‐dimensional data set hypothesizing there are general principles of transcriptomic responses to dietary challenges, i.e.…”