Supplementation with methyl donors during lactation to high-fat-sucrose-fed dams protects offspring against liver fat accumulation when consuming an obesogenic diet

Abstract

Methyl donor supplementation has been reported to prevent obesity-induced liver fat accumulation in adult rats. We hypothesized that this protection could be mediated by perinatal nutrition. For this purpose, we assessed the response to an obesogenic diet (high-fat-sucrose, HFS) during adulthood depending on maternal diet during lactation. Female Wistar rats fed control diet during pregnancy were assigned to four postpartum dietary groups: control, control supplemented with methyl donors (choline, betaine, folic acid, vitamin B12), HFS and HFS supplemented with methyl donors. At weaning, the male offspring was transferred to a chow diet and at week 12th assigned to a control or a HFS diet during 8 weeks. The offspring whose mothers were fed HFS during lactation showed increased adiposity (19%, P<0.001). When fed the HFS diet as adults, offspring whose mothers were HFS supplemented had more body fat (23%, P<0.001) than those from HFS non-supplemented. However, they showed lower liver fat accumulation (-18%, P<0.001). Srebf1, Dnmt1 and Lepr liver mRNA levels increased after adulthood HFS feeding. In those animals HFS fed during adulthood, previous maternal HFS decreased Lepr and Dnmt1 expression levels when compared with c-HFS offspring, while the supplementation of control and HFS-fed dams, respectively, induced higher hepatic Mme and Lepr mRNA levels after adult HFS intake compared with hfs-HFS offspring. In conclusion, maternal HFS diet during lactation influenced the response to an obesogenic diet in the adult progeny. Interestingly, dietary methyl donor supplementation in lactating mothers fed an obesogenic diet reduced liver fat accumulation, but increased adipose tissue storage in adult HFS-fed offspring.

Developmental programming by maternal obesity in 2015: Outcomes, mechanisms, and potential interventions

“…This provides some of the earliest evidence for the impact of human maternal methyl donor dietary intake during pregnancy on life-long epigenetic programming in the offspring. In rodents, maternal dietary supplementation with methyl donors ameliorates the increased body weight gain in offspring of obese dams (Carlin et al, 2013;Cordero et al, 2014) and restores fat preference to control levels in association with normalisation of the methylation status at promoter regions of key genes involved in the central reward system (Carlin et al, 2013).…”

FTO-dependent function of N6-methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice

“…Interestingly, the role of betaine in the rectification of genomic DNA methylation has been suggested as a possible mechanism of the improvements in NAFLD upon betaine supplementation. Furthermore, maternal betaine could protect offspring against hepatic fat accumulation [8] and affect hepatic gene expression through epigenetic mechanism which may include DNA methylation [4]. However, whether betaine could also exert the same protective effects on NAFLD during adolescence has not been reported.…”

Maternal folic acid supplementation with vitamin B 12 deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet

“…No other groups, to our knowledge, have reported on the combined effects of folic acid supplementation with B 12 deficiency in animal models. Most of the published animal studies have focused on maternal folate and/or B 12 restriction or on supplementing maternal diet with multiple methyl nutrients in addition to folic acid and B 12 (19)(20)(21)(22). The former does not recapitulate the high-folate status in the general North American population (6)(7)(8)(9); the latter poses challenges when attempting to delineate the effects of each nutrient on offspring phenotype and its relevance to humans.…”

“…Folate and B 12 are metabolically linked; both vitamins are required for the methionine synthase catalyzed remethylation of homocysteine to methionine. Some studies conducted in rodent models have focused solely on investigating the effects of maternal supplementation with just folic acid or supplementation or deficiency of several B vitamins and other methyl donors on offspring body weight and glucose tolerance (15)(16)(17)(18)(19)(20)(21)(22). Most of those studies were conducted only in male offspring, and little is known about the mechanisms underlying the effects of maternal B vitamin status on offspring adiposity and glucose homeostasis.…”