Faculty Collaboration Database

Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth-restricted rats. FASEB J 2015 Mar;29(3):807-19

Date

11/15/2014

Pubmed ID

25395450

Pubmed Central ID

PMC4422359

DOI

10.1096/fj.14-259614

Scopus ID

2-s2.0-84933038710 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

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.

Author List

Goodspeed D, Seferovic MD, Holland W, Mcknight RA, Summers SA, Branch DW, Lane RH, Aagaard KM

MESH terms used to index this publication - Major topics in bold

Absorptiometry, Photon
Animals
Blood Glucose
DNA Methylation
Dietary Supplements
Female
Fetal Growth Retardation
Glucose Tolerance Test
Insulin-Like Growth Factor I
Metabolic Syndrome
Polymerase Chain Reaction
Pregnancy
Prenatal Exposure Delayed Effects
Promoter Regions, Genetic
Rats
Rats, Sprague-Dawley