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The central role of creatine and polyamines in fetal growth restriction

ABSTRACT: Placental insufficiency is often associated with fetal growth restriction (FGR), a condition associated with both short- and long-term complications for the newborn. In this study, we performed comprehensive transcriptomic and metabolomic analyses to delineate the metabolic profiles that distinguish newborns with FGR from those born with appropriate-for-gestational- age (AGA) status. By comparing our RNA-seq data with placental transcriptome data from the POP dataset, we identified common enrichment categories, notably hypoxia, as well as alterations in creatine and arginine metabolism. In infants with FGR, placental insufficiency tends to promote anaerobic metabolism, resulting in limited ATP production. To counteract this deficiency, arginine is used to synthesise phosphocreatine, an energy-rich compound that is crucial for ATP production. Increased biosynthesis of polyamines addition, our observations show an upregulation of SAT1 acetyltransferase that contributes to decreased concentrations of spermidine and N1-acetylspermidine as well as increased N1,N8-diacetylspermidine concentrations in the placenta of FGR infants. Increased .In summary, our study improves the understanding of metabolic adaptations associated with placental dysfunction in FGR and provides valuable insights for future therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262116 | GEO | 2024/12/06

REPOSITORIES: GEO

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Project description:Worldwide, fetal growth restriction (FGR) affects 7 to 10% of pregnancies, or roughly 20.5 million infants, each year. FGR not only increases neonatal mortality and morbidity but also the risk of obesity in later life. Currently, the molecular mechanisms by which FGR "programs" an obese phenotype are not well understood. Studies demonstrate that FGR females are more prone to obesity compared to males; however, the molecular mechanisms that lead to the sexually dimorphic programming of FGR are not known. Thus, we hypothesized that FGR leads to the sexually dimorphic programming of preadipocytes and reduces their ability to differentiate into mature adipocytes. To test the hypothesis, we utilized a maternal hyperthermia-induced placental insufficiency to restrict fetal growth in sheep. We collected perirenal adipose tissue from male and female near-term FGR and normal-weight fetal lambs (N=4 in each group, 16 total), examined the preadipocytes' differentiation potential, and identified differential mRNA transcript expression in perirenal adipose tissue. Male FGR fetuses have lower cellular density compared to control male fetuses. However, no difference was observed in female FGR fetuses compared to control female fetuses. In addition, the ability of preadipocytes to differentiate into mature adipocytes with fat accumulation was impaired in male FGR fetuses, but this was not observed in female FGR fetuses. Finally, we examined the genes and pathways involved in the sexually dimorphic programming of obesity by FGR. On enrichment of differentially expressed genes in males compared to females, the Thermogenesis KEGG Pathway was downregulated, and the Metabolic and Steroid Biosynthesis KEGG pathways were upregulated. On enrichment of differentially expressed genes in male FGR compared to male control, the Steroid Biosynthesis KEGG Pathway was downregulated, and the PPAR Signaling KEGG pathway was upregulated. No pathways were altered in females in response to growth restriction in perirenal adipose tissue. Thus, the present study demonstrates a sexually dimorphic program in response to growth restriction in sheep fetal perirenal adipose tissue.

Project description:Fetal growth restriction (FGR) is a risk factor for obesity in adult life. Importantly, growth-restricted females are more prone to obesity than males. The mechanisms involved in this sexually dimorphic programming are not known. Previously, we have demonstrated that ambient hyperthermia (40° C) led to placental insufficiency and significant FGR, and the perirenal adipose tissue undergoes sexually dimorphic gene expression. We demonstrated that males undergo significant changes in gene expression with growth restriction. This was not the case in females. We have also demonstrated that the isolated preadipocytes from male FGR (MFGR) have reduced differentiation potential compared to control males & females and female FGR (FFGR). Thus, we hypothesized that growth restriction differentially programs gene expression and genetic pathways in perirenal preadipocytes, which reduces their differentiation potential in male fetuses in a sexually dimorphic manner. We created fetal growth restriction by exposing pregnant sheep to ambient hyperthermia. After isolating preadipocytes from perirenal adipose tissue, we differentiated them following published protocols. We examined the gene expression before and after differentiation from control male, control female, MFGR, and FFGR female. We also compared our data with other published studies in mouse and human preadipocytes. Our results demonstrate that a set of 21 genes altered with preadipocyte differentiation to mature adipocytes is common in adipose tissue from both sexes, humans, mice, and sheep, at different organismal ages (embryonic, fetal, and adult) and different sites (subcutaneous inguinal, pancreatic, perirenal). We also demonstrate that female FFGR fetuses demonstrate all these 21 genes altered similar to control males and females; however, MFGR fetuses have six genes (Dgat2, Fabp4, Lipe, Lrrfip1, Spred3, and Thrsp) that are not changed with preadipocyte differentiation to mature adipocyte. These genes may be responsible for reduced differentiation potential and obesity in FGR males compared to FGR females. Another important finding of the present study is that Lrrfip1, known to be associated with obesity, was upregulated with FGR and requires further investigation. Overall, our studies provide several target genes that may play a crucial role in reducing the risk of MFGR for obesity.

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The central role of creatine and polyamines in fetal growth restriction

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