Use of Glucose, Glutamine, and Fatty Acids for Trophoblast Respiration in Lean Women, Women With Obesity, and Women With Gestational Diabetes

Abstract

Objective Maternal obesity and gestational diabetes mellitus (GDM) are associated with adverse outcomes, particularly with a male fetus. The composition and amount of substrate supplied to the placenta are altered in these conditions. We hypothesized that there are sexually dimorphic differences in utilization of glucose, fatty acids, and glutamine between trophoblast of lean women, women with obesity, and women with GDM. Design Trophoblasts were isolated from term male or female placentas from lean women, women with obesity, or women with GDM (n = 4 to 6 per group), and syncytiotrophoblast formed during 72 hours before measuring mitochondrial respiration by a fuel flex assay (Seahorse XF96 analyzer). Dependency, capacity, and flexibility for use of glucose, glutamine, and fatty acids were measured with western blot of glucose transporter GLUT1, glutaminase, and carnitine palmitoyltransferase 1A. Results Sexual dimorphism in syncytiotrophoblast fuel utilization was seen in women with GDM vs lean women with a significant increase in glucose dependency in males and glucose capacity in females, whereas for glutamine, capacity was significantly decreased in males and females but dependency significantly decreased only in females. Fatty acid dependency and capacity significantly increased in male trophoblast and capacity in female trophoblast of women with GDM vs either lean women or women with obesity. In male but not female trophoblast, flexibility to use all three fuels significantly decreased from lean women to women with obesity and women with GDM. In male trophoblast there were significant associations between GLUT1 and glucose dependency (positive) and flexibility (negative). Conclusions Human syncytiotrophoblast utilizes glutamine for mitochondrial respiration. Utilization of glucose, fatty acids, and glutamine changes in a sexually dimorphic manner with obesity and GDM, predominantly with a male placenta.

Hyperglycemia and gestational diabetes suppress placental glycolysis and mitochondrial function and alter lipid processing

“…Our control group consisted of placentas from non‐obese individuals without GDM, which decreases the potential confounding effect of the relative hyperglycemia observed in obese compared to normal weight pregnant persons 12,47 . Prior studies have demonstrated trophoblast metabolism is affected by GDM independent of obesity 15 . We appreciate that sex is a biologic variable that may affect CTB function.…”

“…Placental oxygen consumption supports ATP production required for protein synthesis, steroid hormone production, and nutrient transport systems by trophoblast cells. Placentas from pregnant persons with GDM exhibit compromised metabolism and lower rates of oxygen consumption 14,15 …”

Differences in Glycolysis and Mitochondrial Respiration between Cytotrophoblast and Syncytiotrophoblast In-Vitro: Evidence for Sexual Dimorphism

“…This ability to switch metabolite substrates depending on nutrient availability is called metabolic flexibility and is a crucial cell survival mechanism when faced with sub-optimal metabolic conditions. We recently showed that in addition to glucose, trophoblast cells can also utilize amino acids, e.g., glutamine, and fatty acids for generation of ATP via the ETC and that the proportions of each used can change with metabolic condition, e.g., obesity or gestational diabetes [ 6 ]. Since, the proliferative CT and differentiated ST have different role in terms of transport, metabolism, and steroid and peptide hormone production, we hypothesized that they might differ in their use of fuel sources and metabolic flexibility.…”

“…This may be linked to the different fetal growth and survival strategies where male fetuses grow larger than female fetuses but are therefore at a greater risk of suffering from adverse pregnancy outcomes if maternal nutrition and placental function are not optimal [ 15 , 16 , 17 ]. We have previously reported maternal obesity, preeclampsia, and gestational diabetes mellitus to be associated with sexually dimorphic effects on energetics and autophagy in the placenta, and have also shown sexual dimorphism in placental antioxidant enzyme activity [ 6 , 18 , 19 , 20 ]. In this study we also investigated if fetal sex had effects on glycolytic and mitochondrial metabolism in CT vs. ST cells from women of a healthy weight.…”

Fetal macrosomia in a Hispanic/Latinx predominant cohort and altered expressions of genes related to placental lipid transport and metabolism

“…However, the reason for this sex disparity remains mysterious to date. In addition to obvious sex differences in nutrition, growth, and metabolism in preterm infants( 34 ), the placenta – transitory but critical fetal tissues to nurturing fetal development and growth – demonstrates sex dimorphism in many aspects including global gene expression( 35 ), steroid hormone production( 36 ), antioxidant buffering capacity ( 37 ), mitochondrial macronutrient metabolism( 38 ), responses to adverse maternal milieu such as obesity, inflammation, hypoxia, GDM, preeclampsia, and other pregnancy related disorders( 39 , 40 ). In the present study, we tried to associate the alteration of placental gene expression with macrosomia bias in males and found that increased expression of FABP4 is coincident with the higher incidence of macrosomia in male fetuses ( Fig.…”