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      Heritable IUGR and adult metabolic syndrome are reversible and associated with alterations in the metabolome following dietary supplementation of 1-carbon intermediates.

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          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.

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          Author and article information

          Journal
          FASEB J.
          FASEB journal : official publication of the Federation of American Societies for Experimental Biology
          FASEB
          1530-6860
          0892-6638
          Jun 2015
          : 29
          : 6
          Affiliations
          [1 ] 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.
          [2 ] 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.
          Article
          fj.14-266387
          10.1096/fj.14-266387
          4447228
          25757570
          a270c579-ad91-4c82-bff4-d4e2b1e5ee0f
          History

          DOHaD,epigenomics,metabolism,placental insufficiency
          DOHaD, epigenomics, metabolism, placental insufficiency

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