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

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.