Sex-Dependent Regulation of Placental Oleic Acid and Palmitic Acid Metabolism by Maternal Glycemia and Associations with Birthweight

Abstract

Pregnancy complications such as maternal hyperglycemia increase perinatal mortality and morbidity, but risks are higher in males than in females. We hypothesized that fetal sex-dependent differences in placental palmitic-acid (PA) and oleic-acid (OA) metabolism influence such risks. Placental explants (n = 22) were incubated with isotope-labeled fatty acids (13C-PA or 13C-OA) for 24 or 48 h and the production of forty-seven 13C-PA lipids and thirty-seven 13C-OA lipids quantified by LCMS. Linear regression was used to investigate associations between maternal glycemia, BMI and fetal sex with 13C lipids, and between 13C lipids and birthweight centile. Placental explants from females showed greater incorporation of 13C-OA and 13C-PA into almost all lipids compared to males. Fetal sex also influenced relationships with maternal glycemia, with many 13C-OA and 13C-PA acylcarnitines, 13C-PA-diacylglycerols and 13C-PA phospholipids positively associated with glycemia in females but not in males. In contrast, several 13C-OA triacylglycerols and 13C-OA phospholipids were negatively associated with glycemia in males but not in females. Birthweight centile in females was positively associated with six 13C-PA and three 13C-OA lipids (mainly acylcarnitines) and was negatively associated with eight 13C-OA lipids, while males showed few associations. Fetal sex thus influences placental lipid metabolism and could be a key modulator of the impact of maternal metabolic health on perinatal outcomes, potentially contributing toward sex-specific adaptions in which females prioritize survival.

Myo-Inositol Moderates Glucose-Induced Effects on Human Placental 13C-Arachidonic Acid Metabolism

“…While the bulk of endogenous 12 C-AA lipids were PEs (32.8%) and PE-Ps (35.4%), for freshly produced 13 C-AA lipids most were TGs (75.1%), with less found in PEs (2.8%), PE-Ps (6.3%) and PIs (5.9%) ( Figure 1 ). This indicates that TGs made up a much greater proportion of newly synthesized AA lipids, while PE, PE-P and PI phospholipids were produced more slowly consistent with previous findings for other fatty acids (Palmitic acid: PA, Oleic acid: OA and Docosahexaenoic acid: DHA) [ 30 , 35 , 36 ].…”

Myo‐inositol alters the effects of glucose, leptin and insulin on placental palmitic acid and oleic acid metabolism

“…However, such effects may be sex-dependent since glucose treatment mainly increased placental 13 C-PA and 13 C-OA acylcarnitines in females (non-GDM and GDM) but not males; this is consistent with previous work where both maternal glycaemia and birthweight were positively associated with placental explant acylcarnitines in females but not males (Watkins et al, 2022c). Glucose treatment also induced increases in 13 C-PA TGs in GDM female placentas, but decreases in non-GDM females, suggesting that prior in vivo exposure to higher maternal glycaemia programs the placental response to glucose.…”

“…Lipids were extracted from placental explants and the media they were incubated in (i.e. 'conditioned media') and analysed as described in Watkins et al (2022c). Placental lipid content was expressed as pmol lipid in explant/mg dry weight of explant, and lipid concentration in conditioned media expressed as pmol lipid in media/mg dry weight of explant.…”

Increasing maternal age associates with lower placental CPT1B mRNA expression and acylcarnitines, particularly in overweight women

“…Placental mRNA expression of carnitine palmitoyltransferases was determined as described previously ( Watkins et al, 2022 ). Briefly, following phenol-chloroform extraction, placental RNA was purified with the RNeasy Mini Kit (Qiagen) and reverse transcribed to cDNA with Superscript III reverse transcriptase (Thermo Fisher Scientific) according to manufacturer’s instructions.…”

“…Lipid extraction and quantification by LC-MS/MS was performed on a subset of 50 placentas using methods similar to previous work on the placental lipidome ( Wong et al, 2021 ; Watkins et al, 2022 ). In brief, approximately 250 mg of each placental sample was freeze-dried, weighed and homogenized in 1 ml phosphate buffered saline.…”