title: CCAAT-enhancer-binding protein β (C/EBPβ) and downstream human placental growth hormone genes are targets for dysregulation in pregnancies complicated by maternal obesity.
abstract: Human chorionic somatomammotropin (CS) and placental growth hormone variant (GH-V) act as metabolic adaptors in response to maternal insulin resistance, which occurs in "normal" pregnancy. Maternal obesity can exacerbate this "resistance," suggesting that CS, GH-V, or transcription factors that regulate their production might be targets. The human CS genes, hCS-A and hCS-B, flank the GH-V gene. A significant decrease in pre-term placental CS/GH-V RNA levels was observed in transgenic mice containing the CS/GH-V genes in a model of high fat diet (HFD)-induced maternal obesity. Similarly, a decrease in CS/GH-V RNA levels was detected in term placentas from obese (body mass index (BMI) ≥ 35 kg/m(2)) versus lean (BMI 20-25 kg/m(2)) women. A specific decrease in transcription factor CCAAT-enhancer-binding protein β (C/EBPβ) RNA levels was also seen with obesity; C/EBPβ is required for mouse placenta development and is expressed, like CS and GH-V, in syncytiotrophoblasts. Binding of C/EBPβ to the CS gene downstream enhancer regions, which by virtue of their position distally flank the GH-V gene, was reduced in placenta chromatin from mice on a HFD and in obese women; a corresponding decrease in RNA polymerase II associated with CS/GH-V promoters was also observed. Detection of decreased endogenous CS/GH-V RNA levels in human placental tumor cells treated with C/EBPβ siRNA is consistent with a direct effect. These data provide evidence for CS/GH-V dysregulation in acute HFD-induced obesity in mouse pregnancy and chronic obesity in human pregnancy and implicate C/EBPβ, a factor associated with CS regulation and placental development.
authors.affiliation: Department of Physiology, Division of Endocrinology and Metabolic Disease, University of Manitoba, Winnipeg R3E 0J9, Canada.
authors.forename: Hana
authors.initials: H
authors.lastname: Vakili
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Savas
authors.initials: S
authors.lastname: Menticoglou
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cattini
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000150:complications / Q000235:genetics*; D000072483:Placenta Growth Factor; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D011257:Pregnancy Proteins / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D055815:Young Adult
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D017931:DNA Primers; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor
keywords: CCAAT-enhancer-binding Protein; Chorionic Somatomammotropin; Enhancers; Gene Expression; Hormones; Obesity; Placenta; Placental Growth Hormone Variant; Transgenic Mice