Department of Physiology and Pathophysiology, University of Manitoba , Winnipeg, Manitoba , Canada.
Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital , Toronto, Ontario , Canada.
Am J Physiol Endocrinol Metab. 2018 Oct 1;315(4):E435-E445. doi: 10.1152/ajpendo.00042.2018. Epub 2018 May 15.
The human (h) placental lactogenic hormone chorionic somatomammotropin (CS) is highly produced during pregnancy and acts as a metabolic adaptor in response to maternal insulin resistance. Maternal obesity can exacerbate this "resistance", and a >75% decrease in CS RNA levels was observed in term placentas from obese vs. lean women. The genes coding for hCS ( hCS-A and hCS-B) and placental growth hormone ( hGH-V) as well as the hCS-L pseudogene and pituitary growth hormone (GH) gene ( hGH-N) are located at a single locus on chromosome 17. Three remote hypersensitive sites (HS III-V) located >28 kb upstream of hGH-N as well as local hCS gene promoter and enhancer regions are implicated in hCS gene expression. A placenta-specific chromosomal architecture, including interaction between HS III-V and hCS but not hGH gene promoters, was detected in placentas from lean women (BMI <25 kg/m) by using the chromosome conformation capture assay. This architecture was disrupted by pre-pregnancy maternal obesity (BMI >35 kg/m), resulting in a predominant interaction between HS III and the hGH-N promoter, which was also observed in nonplacental tissues. This was accompanied by a decrease in hCS levels, which was consistent with reduced RNA polymerase II and CCAAT/enhancer-binding protein-β association with individual hCS promoter and enhancer sequences, respectively. Thus, pre-pregnancy maternal obesity disrupts the placental hGH/CS gene locus chromosomal architecture. However, based on data from obese women who develop GDM, insulin treatment partially recapitulates the chromosomal architecture seen in lean women and positively affects hCS production, presumably facilitating prolactin receptor-related signaling by hCS.
人类（h）胎盘催乳素激素胎盘合体生长激素（CS）在怀孕期间大量产生，作为对母体胰岛素抵抗的代谢适应物。母体肥胖会加剧这种“抵抗”，并且在肥胖和瘦女性的足月胎盘中观察到 CS RNA 水平下降了> 75%。编码 hCS（hCS-A 和 hCS-B）和胎盘生长激素（hGH-V）以及 hCS-L 假基因和垂体生长激素（GH）基因（hGH-N）的基因位于 17 号染色体上的单个基因座上。三个远程超敏位点（HS III-V）位于 hGH-N 的上游> 28 kb，以及局部 hCS 基因启动子和增强子区域，与 hCS 基因表达有关。通过使用染色体构象捕获测定法，在瘦女性（BMI <25 kg/m）的胎盘中检测到胎盘特异性染色体结构，包括 HS III-V 与 hCS 但不与 hGH 基因启动子之间的相互作用。这种结构被孕前母体肥胖（BMI >35 kg/m）破坏，导致 HS III 与 hGH-N 启动子之间的主要相互作用，也观察到非胎盘组织中。这伴随着 hCS 水平的降低，这与 RNA 聚合酶 II 和 CCAAT/增强子结合蛋白-β分别与单个 hCS 启动子和增强子序列的结合减少一致。因此，孕前母体肥胖破坏了胎盘 hGH/CS 基因座的染色体结构。然而，根据患有 GDM 的肥胖女性的数据，胰岛素治疗部分重现了瘦女性的染色体结构，并积极影响 hCS 的产生，这可能通过 hCS 促进催乳素受体相关信号传导。
