title: High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta.
abstract: 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.
authors.affiliation: Research Unit, University Hospital Puerta del Mar, Cádiz, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Visiedo
authors.forename: Fernando
authors.initials: F
authors.lastname: Bugatto
authors.forename: Viviana
authors.initials: V
authors.lastname: Sánchez
authors.forename: Irene
authors.initials: I
authors.lastname: Cózar-Castellano
authors.forename: Jose L
authors.initials: JL
authors.lastname: Bartha
authors.forename: Germán
authors.initials: G
authors.lastname: Perdomo
mesh_terms: D000328:Adult; D000886:Anthropometry; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002950:Citrate (si)-Synthase / Q000378:metabolism; D016640:Diabetes, Gestational / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D002334:Carnitine O-Palmitoyltransferase; D002784:Cholesterol; D002950:Citrate (si)-Synthase; D004852:Epoxy Compounds; D005227:Fatty Acids; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D014280:Triglycerides; C054207:etomoxir
keywords: carnitine palmitoyltransferase I; de novo fatty acid synthesis; esterification of fatty acids; fatty acid oxidation; gestational diabetes mellitus; hyperglycemia; placenta; triglycerides