title: Shared effects of genetic and intrauterine and perinatal environment on the development of metabolic syndrome.
abstract: Genetic and environmental factors, including the in utero environment, contribute to Metabolic Syndrome. Exposure to high fat diet exposure in utero and lactation increases incidence of Metabolic Syndrome in offspring. Using GLUT4 heterozygous (G4+/-) mice, genetically predisposed to Type 2 Diabetes Mellitus, and wild-type littermates we demonstrate genotype specific differences to high fat in utero and lactation. High fat in utero and lactation increased adiposity and impaired insulin and glucose tolerance in both genotypes. High fat wild type offspring had increased serum glucose and PAI-1 levels and decreased adiponectin at 6 wks of age compared to control wild type. High fat G4+/- offspring had increased systolic blood pressure at 13 wks of age compared to all other groups. Potential fetal origins of adult Metabolic Syndrome were investigated. Regardless of genotype, high fat in utero decreased fetal weight and crown rump length at embryonic day 18.5 compared to control. Hepatic expression of genes involved in glycolysis, gluconeogenesis, oxidative stress and inflammation were increased with high fat in utero. Fetal serum glucose levels were decreased in high fat G4+/- compared to high fat wild type fetuses. High fat G4+/-, but not high fat wild type fetuses, had increased levels of serum cytokines (IFN-γ, MCP-1, RANTES and M-CSF) compared to control. This data demonstrates that high fat during pregnancy and lactation increases Metabolic Syndrome male offspring and that heterozygous deletion of GLUT4 augments susceptibility to increased systolic blood pressure. Fetal adaptations to high fat in utero that may predispose to Metabolic Syndrome in adulthood include changes in fetal hepatic gene expression and alterations in circulating cytokines. These results suggest that the interaction between in utero-perinatal environment and genotype plays a critical role in the developmental origin of health and disease.
authors.affiliation: Division of Pediatric Endocrinology, Children's Hospital at Montefiore, Bronx, New York, United States of America. pvuguin@nshs.edu
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Vuguin
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hartil
authors.forename: Michael
authors.initials: M
authors.lastname: Kruse
authors.forename: Harpreet
authors.initials: H
authors.lastname: Kaur
authors.forename: Chia-Lei Vivian
authors.initials: CL
authors.lastname: Lin
authors.forename: Ariana
authors.initials: A
authors.lastname: Fiallo
authors.forename: Alan Scott
authors.initials: AS
authors.lastname: Glenn
authors.forename: Avanee
authors.initials: A
authors.lastname: Patel
authors.forename: Lyda
authors.initials: L
authors.lastname: Williams
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Seki
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Katz
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D001823:Body Composition / Q000502:physiology; D003433:Crosses, Genetic; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D020567:Fetal Weight; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D051275:Glucose Transporter Type 4 / Q000235:genetics; D006579:Heterozygote; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology*; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D058258:Serpin E2 / Q000378:metabolism
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D016207:Cytokines; D051275:Glucose Transporter Type 4; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C495693:Slc2a4 protein, mouse