title: Hypoglycemia, hyperglucagonemia, and fetoplacental defects in glucagon receptor knockout mice: a role for glucagon action in pregnancy maintenance.
abstract: Alterations in insulin signaling as well as insulin action predispose to infertility as well as adverse pregnancy outcomes; however, little is known about the role of glucagon signaling in reproduction. The glucagon receptor knockout (Gcgr(-/-)) mouse created by our laboratory was used to define the role of glucagon signaling in maintaining normal reproduction. In this mouse model, lack of glucagon signaling did not alter the hypothalamic-pituitary-ovarian axis. Pregnant Gcgr(-/-) female mice displayed persistent hypoglycemia and hyperglucagonemia. Gcgr(-/-) pregnancies were associated with decreased fetal weight, increased late-gestation fetal demise, and significant abnormalities of placentation. Gcgr(-/-) placentas contained areas of extensive mineralization, fibrinoid necrosis, narrowing of the vascular channels, and a thickened interstitium associated with trophoblast hyperplasia. Absent glucagon signaling did not alter glycogen content in Gcgr(-/-) placentas but significantly downregulated genes that control growth, adrenergic signaling, vascularization, oxidative stress, and G protein-coupled receptors. Our data suggest that, similarly to insulin, glucagon action contributes to normal female reproductive function.
authors.affiliation: Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Ouhilal
authors.forename: Patricia
authors.initials: P
authors.lastname: Vuguin
authors.forename: Lingguang
authors.initials: L
authors.lastname: Cui
authors.forename: Xiu-Quan
authors.initials: XQ
authors.lastname: Du
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gelling
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Reznik
authors.forename: Robert
authors.initials: R
authors.lastname: Russell
authors.forename: Albert F
authors.initials: AF
authors.lastname: Parlow
authors.forename: Clara
authors.initials: C
authors.lastname: Karpovsky
authors.forename: Nanette
authors.initials: N
authors.lastname: Santoro
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
mesh_terms: D000818:Animals; D005260:Female; D005313:Fetal Death / Q000209:etiology; D005315:Fetal Diseases / Q000209:etiology* / Q000378:metabolism; D005317:Fetal Growth Retardation / Q000209:etiology; D018507:Gene Expression Regulation, Developmental; D005934:Glucagon / Q000097:blood / Q000502:physiology*; D006579:Heterozygote; D007003:Hypoglycemia / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010053:Ovary / Q000187:drug effects / Q000502:physiology; D010903:Pituitary Gland, Anterior / Q000378:metabolism / Q000473:pathology; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D010922:Placenta Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D010929:Placentation; D011247:Pregnancy / Q000502:physiology*; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013480:Superovulation / Q000187:drug effects
chemical_list: D011257:Pregnancy Proteins; D018027:Receptors, Glucagon; D005934:Glucagon