title: Corticosterone alters materno-fetal glucose partitioning and insulin signalling in pregnant mice.
abstract: Glucocorticoids affect glucose metabolism in adults and fetuses, although their effects on materno-fetal glucose partitioning remain unknown. The present study measured maternal hepatic glucose handling and placental glucose transport together with insulin signalling in these tissues in mice drinking corticosterone either from day (D) 11 to D16 or D14 to D19 of pregnancy (term = D21). On the final day of administration, corticosterone-treated mice were hyperinsulinaemic (P < 0.05) but normoglycaemic compared to untreated controls. In maternal liver, there was no change in glycogen content or glucose 6-phosphatase activity but increased Slc2a2 glucose transporter expression in corticosterone-treated mice, on D16 only (P < 0.05). On D19, but not D16, transplacental (3) H-methyl-d-glucose clearance was reduced by 33% in corticosterone-treated dams (P < 0.05). However, when corticosterone-treated animals were pair-fed to control intake, aiming to prevent the corticosterone-induced increase in food consumption, (3) H-methyl-d-glucose clearance was similar to the controls. Depending upon gestational age, corticosterone treatment increased phosphorylation of the insulin-signalling proteins, protein kinase B (Akt) and glycogen synthase-kinase 3β, in maternal liver (P < 0.05) but not placenta (P > 0.05). Insulin receptor and insulin-like growth factor type I receptor abundance did not differ with treatment in either tissue. Corticosterone upregulated the stress-inducible mechanistic target of rapamycin (mTOR) suppressor, Redd1, in liver (D16 and D19) and placenta (D19), in ad libitum fed animals (P < 0.05). Concomitantly, hepatic protein content and placental weight were reduced on D19 (P < 0.05), in association with altered abundance and/or phosphorylation of signalling proteins downstream of mTOR. Taken together, the data indicate that maternal glucocorticoid excess reduces fetal growth partially by altering placental glucose transport and mTOR signalling.
authors.affiliation: Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.
authors.forename: O R
authors.initials: OR
authors.lastname: Vaughan
authors.forename: H M
authors.initials: HM
authors.lastname: Fisher
authors.forename: K N
authors.initials: KN
authors.lastname: Dionelis
authors.forename: E C
authors.initials: EC
authors.lastname: Jeffreys
authors.forename: J S
authors.initials: JS
authors.lastname: Higgins
authors.forename: B
authors.initials: B
authors.lastname: Musial
authors.forename: A N
authors.initials: AN
authors.lastname: Sferruzzi-Perri
authors.forename: A L
authors.initials: AL
authors.lastname: Fowden
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism*; D003345:Corticosterone / Q000494:pharmacology*; D004435:Eating; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; C469992:Ddit4 protein, mouse; D007328:Insulin; D014157:Transcription Factors; D006003:Glycogen; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D003345:Corticosterone