title: Fatty acids alter glycerolipid metabolism and induce lipid droplet formation, syncytialisation and cytokine production in human trophoblasts with minimal glucose effect or interaction.
abstract: The diabetic pregnancy is characterized by maternal hyperglycaemia and dyslipidaemia, such that placental trophoblast cells are exposed to both. The objective was to determine the effects of hyperglycaemia, elevated non-esterified fatty acids (NEFA) and their interactions on trophoblast cell metabolism and function. Trophoblasts were isolated from normal term human placentas and established in culture for 16 h prior to experiments. Glucose utilisation, fatty acid oxidation and fatty acid esterification were determined using radiolabelled metabolic tracer methodology at various glucose and NEFA concentrations. Trophoblast lipid droplet formation including adipophilin mRNA expression, viability, apoptosis, syncytialisation, secretion of hormones and pro-inflammatory cytokines were also assessed. Glucose utilisation via glycolysis was near maximal at the low physiological glucose concentration of 4mM; whereas NEFA esterification into triacylglycerol and diacylglycerol increased linearly with increasing NEFA concentrations without evidence of plateau. Culture of trophoblasts in 0.25 mM NEFA for 24h upregulated fatty acid esterification processes, inhibited fatty acid oxidation, inhibited glycerol release (a marker of lipolysis) and promoted adipophilin and lipid droplet formation, all consistent with upregulation of fatty acid storage and buffering capacity. NEFA also promoted trophoblast syncytialisation and TNFalpha, IL-1beta, IL-6 and IL-10 production without effects on cell viability, apoptosis or hormone secretion. Hyperglycaemia caused intracellular glycogen accumulation and reduced lipid droplet formation, but had no other effects on trophoblast metabolism or function. NEFA have effects on trophoblast metabolism and function, mostly independent of glucose, that may have protective as well as pathophysiological roles in pregnancies complicated by diabetes and/or obesity.
authors.affiliation: Diabetes and Endocrinology Research Unit, Australian National University Medical School at The Canberra Hospital, Garran, ACT, Australia.
authors.forename: A N
authors.initials: AN
authors.lastname: Pathmaperuma
authors.forename: P
authors.initials: P
authors.lastname: Maña
authors.forename: S N
authors.initials: SN
authors.lastname: Cheung
authors.forename: K
authors.initials: K
authors.lastname: Kugathas
authors.forename: A
authors.initials: A
authors.lastname: Josiah
authors.forename: M E
authors.initials: ME
authors.lastname: Koina
authors.forename: A
authors.initials: A
authors.lastname: Broomfield
authors.forename: V
authors.initials: V
authors.lastname: Delghingaro-Augusto
authors.forename: D A
authors.initials: DA
authors.lastname: Ellwood
authors.forename: J E
authors.initials: JE
authors.lastname: Dahlstrom
authors.forename: C J
authors.initials: CJ
authors.lastname: Nolan
mesh_terms: D002449:Cell Aggregation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology*; D008066:Lipolysis; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D019308:Palmitic Acid / Q000378:metabolism*; D000070780:Perilipin-2; D010920:Placenta / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D011247:Pregnancy; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; D012333:RNA, Messenger; D019308:Palmitic Acid; D005947:Glucose