title: The maternal environment programs postnatal weight gain and glucose tolerance of male offspring, but placental and fetal growth are determined by fetal genotype in the Leprdb/+ model of gestational diabetes.
abstract: Mice heterozygous for a signaling-deficient leptin receptor (Leprdb/+ [db/+]) are widely used as a model of gestational diabetes that results in poor fetal outcomes. This study investigated the importance of fetal genotype (db/+) relative to abnormal maternal metabolism for placental function and therefore fetal growth and offspring health. Wild-type (WT) and db/+ females were mated to db/+ and WT males, respectively, generating litters of mixed genotype. Placentas and fetuses were weighed at embryonic day 18.5; offspring weight, hormone levels, glucose tolerance, and blood pressure were assessed at 3 and 6 months. Pregnant db/+, but not WT, dams had impaired glucose tolerance. The db/+ placentas and fetuses were heavier than WT, but the maternal environment had no effect; WT placentas/fetuses from db/+ mothers were no bigger than WT placentas/fetuses carried by WT mothers. Postnatal weight gain, glucose metabolism, and leptin levels were all influenced by offspring genotype. However, maternal environment affected aspects of offspring health because WT male offspring born to db/+ dams were heavier and had worse glucose tolerance than the sex-matched WT offspring of WT mothers. Blood pressure was not affected by maternal or offspring genotype. These data reveal that studies using the db/+ mouse to model outcomes of pregnancy complicated by gestational diabetes should be mindful of the genetically predisposed fetal/postnatal overgrowth. Although inappropriate for dissecting the effect of maternal hyperglycemia on the contribution of placental function to macrosomia, the db/+ mouse may prove useful for investigating mechanisms underlying programming of suboptimal postnatal weight gain and glucose metabolism by an adverse maternal metabolic environment.
authors.affiliation: Maternal and Fetal Health Research Centre, Institute of Human Development (R.N., M.R.D., C.P.S., J.D.A., M.W.) and Centre for Imaging Sciences, Institute of Population Health (J.M.G.), University of Manchester, M13 9PL; and Maternal and Fetal Health Research Centre (R.N., M.R.D., C.P.S., J.D.A., M.W.), St Mary's Hospital, Central Manchester Universities National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, United Kingdom; Gravida (P.N.B.), University of Auckland, Auckland 1142, New Zealand; and Women and Children's Health Research Institute (S.T.D.), University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Raja
authors.initials: R
authors.lastname: Nadif
authors.forename: Mark R
authors.initials: MR
authors.lastname: Dilworth
authors.forename: Colin P
authors.initials: CP
authors.lastname: Sibley
authors.forename: Philip N
authors.initials: PN
authors.lastname: Baker
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.forename: J Martin
authors.initials: JM
authors.lastname: Gibson
authors.forename: John D
authors.initials: JD
authors.lastname: Aplin
authors.forename: Melissa
authors.initials: M
authors.lastname: Westwood
mesh_terms: D000818:Animals; D016640:Diabetes, Gestational / Q000378:metabolism*; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D005838:Genotype; D018149:Glucose Intolerance / Q000235:genetics*; D008297:Male; D051379:Mice; D010929:Placentation; D011247:Pregnancy; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain / Q000235:genetics*
chemical_list: D054411:Receptors, Leptin; C515447:leptin receptor, mouse