Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth‐restricted rats

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 IUGRconferred multigenerational MetS. Pregnant SpragueDawley 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 (D+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 mM). 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 veryLDLs 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.-Goodspeed, D., Seferovic, M. D., Holland, W., Mcknight, R. A., Summers, S. A., Branch, D. W., Lane, R. H., Aagaard, K. M. Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth-restricted rats. FASEB J. 29, 807-819 (2015). www.fasebj.org

Maternal Undernutrition and Long-Term Effects on Hepatic Function

“…In rats, uterine ligation leads to development of the metabolic syndrome in the offspring including type 2 diabetes, dyslipidemia, and hypertriglyceridemia [45][46][47]. Interestingly, many of these symptoms were reciprocated into the F2 generation [48]. These metabolic deficits exist, in part, due to altered glucose transporter expression, impairment of fatty acid metabolism, increased glucocorticoid activity, augmented glucose production, and blunted insulin suppression all within the liver [45,47,[49][50][51].…”

“…Elegant studies in the baboon fetus have demonstrated that 70% undernutrition during pregnancy led to augmented hepatic gluconeogenesis associated with both increased Pck1 mRNA and decreases in the methylation of CpG dinucleotides of the Pck1 promoter [59]. Moreover, uterine ligation has been shown to directly increase DNA methylation in the promoter of hepatic Igf-1 at birth and that this persists into the F2 generation even when F1 IUGR offspring are adequately nourished [48,74]. Interestingly, in this study, supplementation of the diet in the F1 IUGR offspring with folic acid, choline, betaine, vitamin B 12 , and other essential nutrients prevented the methylation of the Igf-1 promoter in the F2 generation along with symptoms of the metabolic syndrome [48].…”

“…Moreover, uterine ligation has been shown to directly increase DNA methylation in the promoter of hepatic Igf-1 at birth and that this persists into the F2 generation even when F1 IUGR offspring are adequately nourished [48,74]. Interestingly, in this study, supplementation of the diet in the F1 IUGR offspring with folic acid, choline, betaine, vitamin B 12 , and other essential nutrients prevented the methylation of the Igf-1 promoter in the F2 generation along with symptoms of the metabolic syndrome [48]. However, caution is necessary in the overall interpretation of these studies given undernutrition-induced alterations in DNA methylation can vary between sexes and within different CpG islands of the same promoter [74].…”

“…But with respect to DNA methylation, the benefits of folic acid appear to be promoter specific given periconceptional intake of folic acid (400 μg/day) led to an increase in DNA methylation of hepatic insulin growth-like factor 2 and, subsequently, low birth weight [82]. As mentioned previously, introduction of a combination of nutrients (i.e., folic acid, vitamin B 12 ) to the diet of IUGR offspring has multigenerational effects given the F2 generation did not exhibit impairments in hepatic and lipid homeostasis [48]. The use of the bile acid tauroursodeoxycholic acid (TUDCA) could be considered as a promising safe therapeutic agent in neonatal life given its ability to reduce ER stress (e.g., protein refolding) and consequentially improve liver insulin sensitivity [83].…”

The Growing Problem of Obesity

“…The authors concluded that in men, early childhood may represent a particularly sensitive period for the development of atherosclerosis. Although these studies were not designed to capture the underlying mechanisms of these “bad memories,” it is plausible that epigenetic changes imparting maladaptive signatures in adipocytes or other metabolic tissues may contribute to these findings 7-10 . What about the reports in ATVB on the consequences of obesity in human subjects?…”