Methyl donor supplementation prevents transgenerational amplification of obesity

Abstract

Background: The obesity epidemic, recognized in developed nations for decades, is now a worldwide phenomenon. All age groups are affected, including women of childbearing age, fueling concern that maternal obesity before and during pregnancy and lactation impairs developmental establishment of body weight regulatory mechanisms in the fetus or infant, causing transgenerational amplification of obesity prevalence and severity. The biological mechanisms underlying such processes remain unknown. Methods: We used agouti viable yellow (A vy ) mice to test the hypothesis that maternal obesity induces transgenerational amplification of obesity. We passed the A vy allele through three generations of A vy /a females and assessed cumulative effects on coat color and body weight. By studying two separate but contemporaneous populations of mice, one provided a standard diet and the other a methyl-supplemented diet that induces DNA hypermethylation during development, we tested whether potential transgenerational effects on body weight might be mediated by alterations in epigenetic mechanisms including DNA methylation. Results: The genetic tendency for obesity in A vy mice was progressively exacerbated when the A vy allele was passed through successive generations of obese A vy females. This transgenerational amplification of body weight was prevented by a promethylation dietary supplement. Importantly, the effect of methyl supplementation on body weight was independent of epigenetic changes at the A vy locus, indicating this model may have direct relevance to human transgenerational obesity. Conclusion: Our results show that in a population with a genetic tendency for obesity, effects of maternal obesity accumulate over successive generations to shift the population distribution toward increased adult body weight, and suggest that epigenetic mechanisms are involved in this process. /a females were mated with a/a males at P56, and their (F2) offspring were treated identically to the F1 generation. In the F3 generation, both females and males were weaned onto the standard mouse diet, and females were not mated. Body weight of all A vy /a mice (F0, F1, F2 and F3) was measured at P180. The digital photographs enabled A vy /a coat color phenotype to be rated by a single observer (RAW) blind to diet group. Coat color was rated as yellow (o5% brown), slightly mottled (X5% but less than half brown), mottled ( approximately half brown), heavily mottled (more than half but p95% brown) or pseudoagouti (495% brown).15 Body composition was measured by dual-energy X-ray absorptiometry (Piximus Series Densitometer, GE Medical Systems, Madison, WI, USA), as per the manufacturers' instructions. We certify that all applicable institutional and governmental regulations concerning the ethical use of animals were followed during this research. The protocol was approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine. Statistical approachesAll data were entered independently into two Excel spreadsheets, which were...

Effects of maternal nutrition on the expression of genomic imprinted genes in ovine fetuses

“…Maternal stressors induce changes in expression of the fetal genome, which can permanently alter the offspring’s physiology, development, metabolism, and growth [50], as reported in mice and rats [51,52]. Understanding the effect of poor maternal nutrition in ovine fetal development is not only relevant to agriculture [53], but also to modeling for human pregnancy and fetal development.…”

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

“…In our study, MD decreased body weight gain and increased total and HDL-cholesterol. In other animal model (agouti mice), Waterland et al [49] described that maternal MD prevented transgenerational increase in adult body weight. Previous investigations had already described the increase of HDL-cholesterol due to betaine [50] and folic acid supplementation [51] in mice and humans, respectively.…”

“…Moreover, IR expression in the hippocampus was decreased by MS and reversed by MD. In this sense, studies in rodents have previously focused on the protective effects of dietary supplementation with methyl donors on obesity [49] and hepatic fat accumulation [29,55], suggesting an improvement of diet-induced insulin resistance by activating IR and the downstream signalling pathways.…”

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

“…Genistein-induced epigenetic alterations seems to share important similarities with those found in intrauterine growth retardation neonates (Einstein et al, 2010), but the magnitude is markedly lower than the differences found between tissues or in cancer. As previously described, perinatal undernutrition (Jousse et al, 2011) or overnutrition (Plagemann et al, 2009), the intake of particular nutrients like methyl donors (Waterland et al, 2008) or PUFA (Kiec-Wilk et al, 2011), or the exposure to endocrine disruptors like bisphenol A (Rubin et al, 2011) are crucial in the in utero modulation of the epigenetic marks (DNA methylation or histone modifications), and more efforts must be made to unravel the epigenetic mechanisms involved in the pathogenesis of obesity and metabolic syndrome, including the doses of each compound, the interactions with the genotype and the period or length of the exposure. One interesting example of possible application of this research is the demonstration that leptin administration during the suckling period has protective effects against later obesity probably by inducing changes in promoter methylation of the hypothalamic POMC gene (Palou et al, 2011).…”

“…A seminal article by Waterland et al (2008) subsequently reported that methyl donor supplementation induces DNA hypermethylation during development and prevents transgenerational amplification of obesity in agouti viable yellow (Avy) mice. After that, many studies have analyzed the epigenetic effects of a diet deficient in methyl donors or with methyl donor supplementation during pregnancy in different metabolic diseases, including altered behavior in offspring (i.e, anxiety) through permanent changes in hippocampal DNA methylation (Konycheva et al, 2011).…”