In vivokinetic study of materno‐fetal fatty acid transfer in obese and normal weight pregnant women

Abstract

Key points Placental structure and function can be modified as a result of maternal obesity affecting materno‐fetal fatty acids (FA) transport. We report for the first time, in humans and in vivo, the kinetics of placental FA transfer in normo‐weight and in normolipemic obese pregnant women using stable isotopes. The administration of different tracer FA with similar behaviour to the mother at different time points allows the collection of kinetic information on materno‐fetal transfer of FA despite only one sample of placenta and cord can be collected per subject. Computational modelling showed a good fit to the data when considering all maternal plasma lipid classes but not when based only on non‐esterified FA. The novel approach using multiple tracer FA administration combined with computational modelling shows a consistent time course of placental tracer FA and predicted total FA accumulation. Abstract We analyse for the first time the in vivo materno‐fetal kinetic transfer of fatty acids (FA) labelled with stable isotopes in control and obese (OB) pregnant women. Labelled FA with a similar metabolism (stearic acid: 13C‐SA; palmitic acid: 13C‐PA; oleic acid: 13C‐OA) were orally administered at −4 h, −8 h and −12 h, respectively prior to elective caesarean section to 10 pregnant women with a body mass index >30 (OB) and 10 with a body mass index in the range 20–25 (NW). Placenta, venous and arterial cord blood were collected obtaining a wide range of FA enrichments. A combined experimental and computational modelling analysis was applied. FA fractional synthesis rate (FSR) in placenta was 11–12% h–1. No differences were observed between NW and normo‐lipidemic OB. It was not possible to estimate FA FSR in cord blood with this oral bolus dose approach. Computational modelling demonstrated a good fit to the data when all maternal plasma lipid classes were included but not with modelling based only on the non‐esterified FA fraction. The estimated materno‐fetal 13C‐FA transfer was ∼1%. In conclusion, our approach using multiple 13C‐FA tracers allowed us to estimated FSR in placental/maternal plasma but not in fetal/maternal compartments. Computational modelling showed a consistent time course of placental 13C‐FA transfer and predicted total fetal FA accumulation during the experiment. We conclude that, in addition to non‐esterified FA fraction in the maternal circulation, maternal plasma very low‐density lipoprotein and other lipoproteins are important contributors to placental FA transfer to the fetus.

Development and validation of a gas chromatography–mass spectrometry method to analyze octanoate enrichments at low concentrations in human plasma

“…The procedure was highly similar to the gold-standard method for fatty acid enrichment analysis, where fatty acids are extracted, derivatized by addition of 3 M methanolic HCl, and incubated for 60 min at 90°C [12,13]. Except for the extraction and derivatizing reagent, these reaction conditions were kept the same.…”

“…With this method, the total plasma octanoate enrichment is analyzed. We altered our current methylation protocol [12,13] to facilitate isobutylation, which in comparison with methylation reduced the volatility of the derivatized octanoate, thereby reducing the risk of losses of the analyte during sample preparation. Direct derivatization in plasma limits the risk of contamination and, therefore, has improved accuracy and reproducibility.…”

Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments

“…MBPK is the combination of classical pharmacokinetic modeling with elements describing the main mechanisms working in the system. MBPK founds on the mass conservation law and it has been used to inform several biological systems (Lofthouse et al, 2015;Perazzolo et al, 2015;Perazzolo et al, 2017;Perazzolo, 2017;Gázquez et al, 2019). Modeling procedure consisted of four steps: 1) Model structure building to represent the absorption mechanisms able to explain the long-acting pharmacokinetics exhibited by the nanoformulation; 2) Identifying the model parameters with mouse data; 3) Scaling the mouse model to get an NHP model; 4) Simulate a reference dose in the NHP model and observe results.…”

What's so special about lipid transport in the human placenta?

“…in this issue of The Journal of Physiology are the most thorough so far published (Gázquez et al . ). Their clever experimental design provided enough temporal concentration information to allow the estimation of fractional synthesis rate of free fatty acids and accumulation rates by the placenta in vivo .…”

“…While Kolahi et al have estimated the uptake kinetics of free fatty acids in vitro (Kolahi et al 2018), little is known about the kinetics of fatty acid metabolism by the human placenta under physiological conditions. The kinetic studies reported by Gázquez et al in this issue of The Journal of Physiology are the most thorough so far published (Gázquez et al 2019). Their clever experimental design provided enough temporal concentration information to allow the estimation of fractional synthesis rate of free fatty acids and accumulation rates by the placenta in vivo.…”