title: Heritable IUGR and adult metabolic syndrome are reversible and associated with alterations in the metabolome following dietary supplementation of 1-carbon intermediates.
abstract: Metabolic syndrome (MetS), following intrauterine growth restriction (IUGR), is epigenetically heritable. Recently, we abrogated the F2 adult phenotype with essential nutrient supplementation (ENS) of intermediates along the 1-carbon pathway. With the use of the same grandparental uterine artery ligation model, we profiled the F2 serum metabolome at weaning [postnatal day (d)21; n = 76] and adulthood (d160; n = 12) to test if MetS is preceded by alterations in the metabolome. Indicative of developmentally programmed MetS, adult F2, formerly IUGR rats, were obese (621 vs. 461 g; P < 0.0001), dyslipidemic (133 vs. 67 mg/dl; P < 0.001), and glucose intolerant (26 vs. 15 mg/kg/min; P < 0.01). Unbiased gas chromatography-mass spectrometry (GC-MS) profiling revealed 34 peaks corresponding to 12 nonredundant metabolites and 9 unknowns to be changing at weaning [false discovery rate (FDR) < 0.05]. Markers of later-in-life MetS included citric acid, glucosamine, myoinositol, and proline (P < 0.03). Hierarchical clustering revealed grouping by IUGR lineage and supplementation at d21 and d160. Weanlings grouped distinctly for ENS and IUGR by partial least-squares discriminate analysis (PLS-DA; P < 0.01), whereas paternal and maternal IUGR (IUGR(pat)/IUGR(mat), respectively) control-fed rats, destined for MetS, had a distinct metabolome at weaning (randomForest analysis; class error < 0.1) and adulthood (PLS-DA; P < 0.05). In sum, we have found that alterations in the metabolome accompany heritable IUGR, precede adult-onset MetS, and are partially amenable to dietary intervention.
authors.affiliation: Departments of *Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Cell Biology, Molecular and Human Genetics, and Molecular Physiology and Biophysics, and Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Metabolomics Core, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Maxim D
authors.initials: MD
authors.lastname: Seferovic
authors.affiliation: Departments of *Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Cell Biology, Molecular and Human Genetics, and Molecular Physiology and Biophysics, and Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Metabolomics Core, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Goodspeed
authors.affiliation: Departments of *Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Cell Biology, Molecular and Human Genetics, and Molecular Physiology and Biophysics, and Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Metabolomics Core, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Derrick M
authors.initials: DM
authors.lastname: Chu
authors.affiliation: Departments of *Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Cell Biology, Molecular and Human Genetics, and Molecular Physiology and Biophysics, and Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Metabolomics Core, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Krannich
authors.affiliation: Departments of *Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Cell Biology, Molecular and Human Genetics, and Molecular Physiology and Biophysics, and Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Metabolomics Core, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Gonzalez-Rodriguez
authors.affiliation: Departments of *Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Cell Biology, Molecular and Human Genetics, and Molecular Physiology and Biophysics, and Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Metabolomics Core, University of Utah, Salt Lake City, Utah, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Cox
authors.affiliation: Departments of *Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Cell Biology, Molecular and Human Genetics, and Molecular Physiology and Biophysics, and Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA; and Department of Biochemistry and Metabolomics Core, University of Utah, Salt Lake City, Utah, USA aagaardt@bcm.edu.
authors.forename: Kjersti M
authors.initials: KM
authors.lastname: Aagaard
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D019343:Citric Acid / Q000097:blood / Q000378:metabolism; D019587:Dietary Supplements; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005944:Glucosamine / Q000097:blood / Q000378:metabolism; D018149:Glucose Intolerance / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods*; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014886:Weaning
chemical_list: D019343:Citric Acid; D005944:Glucosamine
keywords: DOHaD; epigenomics; metabolism; placental insufficiency