| Title: | Chronic Adrenergic Signaling Causes Abnormal RNA Expression of Proliferative Genes in Fetal Sheep Islets |
| Author(s): | Kelly AC; Bidwell CA; Chen X; Macko AR; Anderson MJ; Limesand SW; |
| Address: | "School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona. Department of Animal Sciences, Purdue University, West Lafayette, Indiana. Chongqing Key Laboratory of Forage & Herbivore, College of Animal Science and Technology, Southwest University, Chongqing, China" |
| ISSN/ISBN: | 1945-7170 (Electronic) 0013-7227 (Print) 0013-7227 (Linking) |
| Abstract: | "Intrauterine growth restriction (IUGR) increases the risk of developing diabetes in later life, which indicates developmental programming of islets. IUGR fetuses with placental insufficiency develop hypoxemia, elevating epinephrine and norepinephrine (NE) concentrations throughout late gestation. To isolate the programming effects of chronically elevated catecholamines, NE was continuously infused into normally grown sheep fetuses for 7 days. High plasma NE concentrations suppress insulin, but after the NE infusion was terminated, persistent hypersecretion of insulin occurred. Our objective was to identify differential gene expression with RNA sequencing (RNAseq) in fetal islets after chronic adrenergic stimulation. After determining the NE-regulated genes, we identified the subset of differentially expressed genes that were common to both islets from NE fetuses and fetuses with IUGR to delineate the adrenergic-induced transcriptional responses. A portion of these genes were investigated in mouse insulinoma (Min6) cells chronically treated with epinephrine to better approximate the beta-cell response. In islets from NE fetuses, RNAseq identified 321 differentially expressed genes that were overenriched for metabolic and hormone processes, and the subset of 96 differentially expressed genes common to IUGR islets were overenriched for protein digestion, vitamin metabolism, and cell replication pathways. Thirty-eight of the 96 NE-regulated IUGR genes changed similarly between models with functional enrichment for proliferation. In Min6 cells, chronic epinephrine stimulation slowed proliferation and augmented insulin secretion after treatment. These data establish molecular mechanisms underlying persistent adrenergic stimulation in hyperfunctional fetal islets and identify a subset of genes dysregulated by catecholamines in IUGR islets that may represent programming of beta-cell proliferation capacity" |
| Keywords: | "Adrenergic alpha-Agonists/administration & dosage/pharmacology Animals Cell Line, Tumor Female Fetal Growth Retardation/genetics Fetus/*metabolism Gene Expression Profiling/*methods Gene Expression Regulation, Developmental/*drug effects High-Throughput N;" |
| Notes: | "MedlineKelly, Amy C Bidwell, Christopher A Chen, Xiaochuan Macko, Antoni R Anderson, Miranda J Limesand, Sean W eng R01 DK084842/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2018/08/21 Endocrinology. 2018 Oct 1; 159(10):3565-3578. doi: 10.1210/en.2018-00540" |
