Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth-restricted rats.
Intrauterine growth restriction (IUGR) confers heritable alterations in DNA methylation, rendering risk of adult metabolic syndrome (MetS). Because CpG methylation is coupled to intake of essential nutrients along the one-carbon pathway, we reasoned that essential nutrient supplementation (ENS) may abrogate IUGR-conferred multigenerational MetS. Pregnant Sprague-Dawley rats underwent bilateral uterine artery ligation causing IUGR in F1. Among the F2 generation, IUGR lineage rats were underweight at birth (6.7 vs. 8.0 g, P < 0.0001) and obese by adulthood (p160: 613 vs. 510 g; P < 0.0001). Dual energy X-ray absorptiometry studies revealed increased central fat mass (Δ+40 g), accompanied by dyslipidemic (>30% elevated, P < 0.05) serum triglycerides (139 mg/dl), very-LDLs (27.8 mg/dl), and fatty acids (632 µM). Hyperglycemic-euglycemic clamp studies and glucose tolerance testing revealed insulin resistance. Conversely, IUGR lineage ENS-fed rats did not manifest MetS, with significantly lower body weight (p160: 410 g), >5-fold less central fat mass, normal hepatic glucose efflux, and >70% reduced circulating triglycerides and very-LDLs compared with IUGR control-fed F2 offspring (P < 0.01). Moreover, increased methylation of the IGF-1 P2 transcriptional start site among IUGR lineage F2 offspring was reversed in ENS (P < 0.04). This is an initial demonstration that supplementation along the one-carbon pathway abrogates adult morbidity and associated epigenomic modifications of IGF-1 in a rodent model of multigenerational MetS.
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Danielle
D
Goodspeed
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Maxim D
MD
Seferovic
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
William
W
Holland
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Robert A
RA
Mcknight
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Scott A
SA
Summers
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
D Ware
DW
Branch
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
Robert H
RH
Lane
*Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA; Department of Internal Medicine, Department of Pediatrics, and Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah, USA; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore; and Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA aagaardt@bcm.tmc.edu.
Kjersti M
KM
Aagaard
D015502:Absorptiometry, Photon; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D019175:DNA Methylation; D019587:Dietary Supplements; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D024821:Metabolic Syndrome / Q000209:etiology / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000517:prevention & control*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D007334:Insulin-Like Growth Factor I
IGF-1; epigenomics; methyl donors; obesity; one-carbon pathway