Biology subjects

Regnault, T.

Publications and source records attributed to Regnault, T..

7 recordsLinked to original sources

bioRxiv2026

Altered Placental Pyruvate Metabolism in Spontaneous Intrauterine Growth Restricted near-term Pregnant Guinea Pigs

Abstract1IUGR is associated with increased risk of fetal compromise, yet can be difficult to detect and phenotype with routine clinical surveillance. Given placental insufficiency and hypoxia can remodel placental energy metabolism, methods that directly assess placental metabolic function may improve identification and phenotyping of growth-restricted pregnancies. We combined structural, body composition, and hyperpolarized metabolic MRI to characterize a near-term spontaneous IUGR (spIUGR) phenotype in the guinea pig. Twenty-two pregnant guinea pig sows (71 fetuses) underwent 1H and hyperpolarized 13C MRI at 60 {+/-} 1 days gestation to quantify fetal and placental volumes, maternal/fetal body composition, and quantify placental pyruvate metabolism. Fetuses were classified as spIUGR when [≥] 3 of 5 established markers were present (body weight, brain-body, brain-liver, brain-placenta ratios, and body weight relative to pregnancy mean); corresponding volume cut-offs were derived from weight cut-offs. MRI-derived fetal and placental volumes correlated strongly with collection weights and classified spIUGR consistently with weight-based criteria. Maternal adiposity (subcutaneous and visceral) was inversely associated with fetal adipose tissue volume, and maternal visceral fat PDFF was negatively associated with fetal adipose PDFF. Hyperpolarized MRI demonstrated IUGR phenotype-dependent placental pyruvate routing: LPR increased with asymmetric (brain-sparing) growth, showing a positive association with brain-body volume ratio (p = 0.02) and brain-body weight ratio (p = 0.04). In contrast, BPR was not significantly related to brain-body ratios (p = 0.09-0.11) but was inversely associated with absolute fetal size (body volume and weight, p = 0.02). These findings validate MRI volumetry for non-invasive identification of placental insufficiency spIUGR and link growth restriction severity and asymmetry to distinct placental metabolic signatures measurable in vivo.

biophysics↗

bioRxiv2025

Altered placental morphology and metabolomic profile in as-sociation with uncomplicated metabolically healthy obese pregnancy

Metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in pregnancy represent two distinct cardiometabolic populations, each potentially necessitating alternative clinical management. However, the understanding of the unique physiological effects of uncomplicated MHO or MUO on fetoplacental growth and metabolism remains limited. This study aimed to identify changes in placental morphology and metabolites concerning maternal obesity, independent of pregnancy-related cardiometabolic complications. Placentae from women with a pre-pregnancy body mass index (BMI) <25 kg/m2 (control; n = 15) and women with MHO (pre-pregnancy BMI >30 kg/m2 with no cardiometabolic diseases; n = 15) were analysed for indices of placental growth and untargeted metabolomics. Complementary measures of pro-inflammatory and antioxidant genes, as well as antioxidant proteins, enzymes, and lipid peroxidation markers were conducted. A clear placentomegaly without histopathological changes was observed in uncomplicated MHO pregnancies. The metabolite 3-aminoisobutanoic acid emerged as the top-ranked feature distinguishing MHO from control placentae, and cysteine, methionine, and vitamin B6 metabolism pathways were among the most distinct signatures identified. These findings illustrate an altered placental morphology and metabolomic profile specific to uncomplicated MHO, offering new insights into how obesity without cardiometabolic complications influences fetoplacental growth and metabolism. They also represent a crucial first step towards marker identification for MHO pregnancies and underscore the importance of alternative care pathways when obesity is present but metabolic comorbidities are absent.

physiology↗

bioRxiv2025

Placenta hIGF1 nanoparticle treatment in guinea pigs mitigates fetal sex dependent FGR-associated effects on kidney structure and blood pressure-related signaling pathways

Fetal development in an adverse in utero environment significantly increases the risk of hypertension and cardiovascular disease. The kidneys play a pivotal role in the regulation of blood pressure and cardiovascular function, and perturbations in kidney structure and molecular profile are often demonstrated in offspring born fetal growth restricted (FGR). The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate FGR-associated dysregulation of fetal kidney development. Using the guinea pig maternal nutrient restriction (MNR) model, we improved placenta efficiency and fetal weight following three placental administrations of a non-viral polymer-based nanoparticle gene therapy from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal kidney tissue was collected near-term at gestational day 60. Differences in kidney structure, glomeruli size and gene expression of extracellular matrix (ECM) remodeling and blood pressure regulation-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. We speculate that mitigating the FGR-associated changes in kidney architecture and molecular profiles might confer protection against increased susceptibility to aberrant kidney physiology in later-life. Overall, this work opens avenues for future research to assess the long-term impact of the placental hIGF1 nanoparticle gene therapy on cardiovascular function in offspring.

physiology↗

bioRxiv2024

Placental hIGF1 nanoparticle gene therapy in guinea pigs ameliorates fetal growth restriction-associated changes in hepatic lipid and glucose metabolism-related signaling pathways in a fetal sex-specific manner

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, non-alcoholic fatty liver diseases and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency was significantly improved following three administrations of a non-viral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (gestational day 35) until gestational day 52. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (hIGF1) in placenta trophoblast. Fetal liver tissue was collected near-term at gestational day 60. Fetal sex specific differences in liver gene and protein expression of pro-fibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental hIGF1 nanoparticle treatment. Increased plasma bilirubin, and indirect measure of hepatic activity, was also increased with placental hIGF1 nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing Control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later-life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements. NEW AND NOTEWORTHYA placenta-specific non-viral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later-life. This knowledge may have implications towards removing predispositions that increase the risk of metabolic diseases including diabetes, dyslipidemia and non-alcoholic fatty liver disease in later life.

physiology↗

bioRxiv2024

Fructose consumption in pregnancy and associations with maternal and offspring hepatic and whole-body adiposity: a scoping review.

BackgroundFructose is a major component in the Western diet, and its increased intake has been linked to adverse metabolic health, including impaired hepatic function and increased adiposity. The early life period, including preconceptionally, pregnancy and the newborn period, are critical periods in determining later metabolic health. However, the impact of excess fructose intake during this time on maternal, fetal, and offspring hepatic and whole-body adiposity, are ill defined. ObjectivesTo understand the effects of maternal fructose consumption pre- and during pregnancy on maternal, fetal and offspring hepatic and whole-body adiposity. MethodsA systematic search of MEDLINE, EMBASE, and CENTRAL was performed up to August 23, 2022, to identify studies that focused on maternal fructose consumption pre- and during pregnancy on hepatic and whole-body adiposity in the mother, fetus, and offspring. Citations, abstracts, and full texts were screened in duplicate. Hepatic adiposity was defined as elevated hepatic triglycerides or overall hepatic fat accumulation. Whole-body adiposity was defined as increased adipose tissue or adipocyte hypertrophy. ResultsAfter screening 2334 citations, 33 experimental studies reporting maternal fructose consumption pre- and during pregnancy in rodents were included. Prenatal fructose exposure was associated with maternal (9 out of 12) and offspring (6 out of 10) whole-body adiposity. A high proportion of studies (13 out of 14) supported the association between fructose during pregnancy and increased maternal hepatic adiposity. Fetal hepatic adiposity and elevated expression of hepatic lipogenic proteins were noted in four studies. Offspring hepatic adiposity was supported in 14 of the 17 articles that discussed hepatic results, with five studies demonstrating more severe effects in female offspring. ConclusionsFructose consumption during pregnancy in rodent models is associated with maternal, fetal, and offspring hepatic, whole-body adiposity and underlying sex-specific effects. There are no human fructose studies and its effects in the early life period. Registration numberH8F26 on Open Science Framework

developmental biology↗

bioRxiv2023

High Maternal Adiposity During Pregnancy Programs an Imbalance in the Lipidome and Predisposes to Diet-induced Hepatosteatosis in the Offspring

BackgroundExposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. ResultsFemales heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high fat/fructose diet (HFFD) compared to Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams compared to CD or HFFD-Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb. dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic PUFA levels compared to control offspring. Changes to saturated fatty acids (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and {Delta}9 desaturase activity. ConclusionHigh maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

developmental biology↗

bioRxiv2020

Telomerase inhibition causes premature senescence of fetal guinea pig muscle cells

Premature senescence in low birth weight rodents is associated with later life metabolic disease, including the development of insulin resistance. Telomerase, a reverse transcriptase enzyme with telomeric and non-telomeric functions, is present at high levels during development to maintain and repair long telomere lengths and to protect cells from oxidative stress-induced growth arrest. Adverse In utero environments are often associated with increased reactive oxygen species (ROS), and ROS have been documented to impair/alter telomerase function. We postulate that telomerase protects cells against oxidative stress-induced damage, and its inhibition could lead to premature senescence. A primary cell line of fetal guinea pig muscle cells was differentiated under high (20%) and low (1-2%) oxygen concentrations and telomerase activity was pharmacologically inhibited using a synthetic tea catechin. Following 48 hours, ROS detection was conducted with MitoSOX, Mitotracker and 6-carboxy-2,7-dichlorodihydrofluorescein diacetate staining. Cells cultured at 20% O2 and treated with a telomerase activity inhibitor displayed reduced cell growth rates and increased levels of senescence markers, including p21 and p53. Telomeric DNA damage, measured by phosphorylated-{gamma}H2A.X staining at telomeres, was significantly increased in cells cultured at all oxygen concentrations with telomerase inhibition. Telomerase inhibition altered metabolic signaling (e.g. mTOR, p66Shc) and increased mitochondrial ROS levels. Telomerase may protect cells during development from adverse in utero environments that cause premature senescence.

cell biology↗