Placentas of women with
gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high
glucose levels reduce mitochondrial
fatty acid oxidation (FAO) and increase
triglyceride accumulation in human placenta. To test this hypothesis, we measured FAO,
fatty acid esterification, de novo
fatty acid synthesis,
triglyceride levels, and
carnitine palmitoyltransferase activities (
CPT) in placental explants of women with GDM or no
pregnancy complication. In women with GDM, FAO was reduced by ~30% without change in mitochondrial content, and
triglyceride content was threefold higher than in the control group. Likewise, in placental explants of women with no complications, high
glucose levels reduced FAO by ~20%, and esterification increased linearly with increasing
fatty acid concentrations. However, de novo
fatty acid synthesis remained unchanged between high and low
glucose levels. In addition, high
glucose levels increased
triglyceride content approximately twofold compared with low
glucose levels. Furthermore,
etomoxir-mediated inhibition of FAO enhanced esterification capacity by ~40% and elevated
triglyceride content 1.5-fold in placental explants of women, with no complications. Finally, high
glucose levels reduced
CPT I activity by ~70% and phosphorylation levels of
acetyl-CoA carboxylase by ~25% in placental explants of women, with no complications. We reveal an unrecognized regulatory mechanism on placental
fatty acid metabolism by which high
glucose levels reduce mitochondrial FAO through inhibition of
CPT I, shifting flux of
fatty acids away from oxidation toward the esterification pathway, leading to accumulation of placental
triglycerides.