Daniel S. Lupu

High fat diet-induced maternal obesity alters fetal hippocampal development.

The importance of maternal nutrition for fetal brain development is increasingly recognized. Previous studies have suggested that maternal obesity or maternal exposure to obesogenic diets may permanently alter brain structure and function in the offspring. To test whether maternal exposure to a high‐fat diet, prior and during gestation, alters fetal hippocampal development, we fed 8‐week old C57BL/6 females with a high‐fat diet (60% calories from fat) for 10 weeks prior to matting and 17 days after. Fetal brains at embryonic day E17 were used to determine developmental changes in the hippocampus. We report that maternal exposure to the high‐fat diet induced small for gestational age (SGA) status and fetal resorption. The proliferation of neural progenitors was increased in the neuroepithelium from hippocampus and cortex in fetuses from mothers fed the high‐fat diet when compared to controls, but decreased within the dentate gyrus (DG). Apoptosis in the hippocampus was decreased (Ammons Horn and fimbria). The differentiation of calretinin‐positive neurons within the DG was also decreased.

Perinatal manipulation of α-linolenic acid intake induces epigenetic changes in maternal and offspring livers

Previous studies indicated that the intake of α‐linolenic acid (ALA) can alter the concentration of both ω‐6 and ω‐3 fatty acids in both mother and offspring, with consequences on postnatal brain development. This study describes the association between maternal ALA availability during gestation and lactation, and alterations in the Fads2 DNA methylation in both maternal and offspring livers, at the end of lactation period. Both Fads2 promoter and intron 1 DNA methylation were increased in the groups receiving postnatal flaxseed oil containing 50% ALA (mothers or pups), while bivariate analysis indicated a significant association of the Fads2 epigenetic status in the liver between each mother and its offspring. In addition, Fads2 expression was negatively correlated with promoter methylation at the individual level in maternal livers (P<0.05). This study also indicated that the interplay between ALA availability during gestation and lactation can differentially alter the expression of desaturases and elongases involved in ω‐6 and ω‐3 metabolic pathways. In summary, when considering the perinatal dietary ALA requirements in mice, both gestation and lactation periods should be considered as having distinct roles in modulating the metabolism of ω‐6 and ω‐3 fatty acids in maternal mouse livers.—Niculescu, M. D., Lupu, D. S., Craciunescu, C. N. Perinatal manipulation of α‐linolenic acid intake induces epigenetic changes in maternal and offspring livers. FASEB J. 27, 350–358 (2013). www.fasebj.org

Nutritional influence on epigenetics and effects on longevity.

Purpose of reviewThis review synthesizes recently published information regarding nutrition and its impact upon epigenetically mediated mechanisms involved in longevity and aging. Recent findingsRecent studies enriched considerably our understanding of the relationship between aging and gene–nutrient interactions that continuously shape our phenotype. Epigenetic mechanisms play an important role in mediating between the nutrient inputs and the ensuing phenotypic changes throughout our entire life and seem to be responsible, in part, for the biological changes that occur during aging. Less is known about the epigenetic role that nutrients have in directly influencing longevity and aging. However, recent studies clearly indicated that because nutrition modulates epigenetic events associated with various diseases (e.g., cancer, obesity, and diabetes), there is at least an indirect epigenetic link between nutrition and longevity and, therefore, biologic plausibility to hypothesize the epigenetic role of nutrition in altering longevity. Apart from limited human studies, promising animal studies brought us much closer to understanding how nutrition could have such an impact upon longevity and aging. SummaryComplex epigenetic mechanisms are involved in aging and longevity, directly or indirectly via disease mechanisms. Nutrition has a strong impact upon epigenetic processes and, therefore, holds promise in having important roles in regulating longevity and aging.

Maternal α-linolenic acid availability during gestation and lactation alters the postnatal hippocampal development in the mouse offspring

The availability of ω‐3 polyunsaturated fatty acids is essential for perinatal brain development. While the roles of docosahexaenoic acid (the most abundant ω‐3 species) were extensively described, less is known about the role of α‐linolenic acid (ALA), which is the initial molecular species undergoing elongation and desaturation within the ω‐3 pathways. This study describes the association between maternal ALA availability during gestation and lactation, and alterations in hippocampal development (dentate gyrus) in the mouse male offspring, at the end of lactation (postnatal day 19, P19). Postnatal ALA supplementation increased cell proliferation (36% more proliferating cells compared to a control group) and early neuronal differentiation, while postnatal ALA deficiency increased cellular apoptosis within the dentate gyrus of suckling pups (61% more apoptotic cells compared to a control group). However, maternal ALA deficiency during gestation prevented the increased neurogenesis induced by postnatal supplementation. Fatty acid analysis revealed that ALA supplementation increased the concentration of the ω‐3 species in the maternal liver and serum, but not in the brain of the offspring, excepting for ALA itself. Interestingly, ALA supplementation also increased the concentration of dihomo γ‐linolenic acid (a ω‐6 species) in the P19 brains, but not in maternal livers or serum. In conclusion, postnatal ALA supplementation enhances neurogenesis in the dentate gyrus of the offspring at postnatal day 19, but its beneficial effects are offset by maternal ALA deficiency during gestation. These results suggest that ALA is required in both fetal and postnatal stages of brain development.

Perinatal α-linolenic acid availability alters the expression of genes related to memory and to epigenetic machinery, and the Mecp2 DNA methylation in the whole brain of mouse offspring.

Many animal and human studies indicated that dietary ω‐3 fatty acids could have beneficial roles on brain development, memory, and learning. However, the exact mechanisms involved are far from being clearly understood, especially for α‐linolenic acid (ALA), which is the precursor for the ω‐3 elongation and desaturation pathways. This study investigated the alterations induced by different intakes of flaxseed oil (containing 50% ALA), during gestation and lactation, upon the expression of genes involved in neurogenesis, memory‐related molecular processes, and DNA methylation, in the brains of mouse offspring at the end of lactation (postnatal day 19, P19). In addition, DNA methylation status for the same genes was investigated. Maternal flaxseed oil supplementation during lactation increased the expression of Mecp2, Ppp1cc, and Reelin, while decreasing the expression of Ppp1cb and Dnmt3a. Dnmt1 expression was decreased by postnatal flaxseed oil supplementation but this effect was offset by ALA deficiency during gestation. Mecp2 DNA methylation was decreased by maternal ALA deficiency during gestation, with a more robust effect in the lactation‐deficient group. In addition, linear regression analysis revealed positive correlations between Mecp2, Reelin, and Ppp1cc, between Gadd45b, Bdnf, and Creb1, and between Egr1 and Dnmt1, respectively. However, there were no correlations, in any gene, between DNA methylation and gene expression. In summary, the interplay between ALA availability during gestation and lactation differentially altered the expression of genes involved in neurogenesis and memory, in the whole brain of the offspring at the end of lactation. The Mecp2 epigenetic status was correlated with ALA availability during gestation. However, the epigenetic status of the genes investigated was not associated with transcript levels, suggesting that either the regulation of these genes is not necessarily under epigenetic control, or that the whole brain model is not adequate for the exploration of epigenetic regulation in the context of this study.

Low dose Flaxseed Oil Supplementation Alters the Fatty Acids Profile and the Progression of Metabolic Syndrome in Men without Adequate Medical Treatment

Many studies indicated that increased intakes of ω-3 fatty acids could positively impact the progression of metabolic syndrome (MS). This study aimed to characterize the clinical and biochemical changes initiated by a low-dose flaxseed oil supplementation upon the evolution of metabolic syndrome in men without adequate medical treatment. In a double blind, randomized study, middle-aged men with metabolic syndrome, who were not able to follow the prescribed medical treatment, were assigned to either a group receiving daily 2.4 g flaxseed oil, or the same amount of corn oil, for 90 days, respectively. Analysis of variance, logistic, and bivariate fit analyses were used to describe the statistical significance of parameters changed by either treatment (within and between group comparisons), between the start and end of treatment. While none of the five diagnostic criteria for MS were differently altered between groups and time points, changes in body mass index (BMI) and insulin resistance were significantly correlated with the treatment received. Subjects receiving flaxseed oil registered no increase in BMI, as compared to an increased BMI registered in the corn oil group (+1.12 ± 0.63, p 0.05 ratios between start and end of study, respectively). The analysis of total serum fatty acid profiles indicated, among other changes, significance for time-treatment interaction for serum 11-eicosenoic acid (p<0.05). Other correlations on inflammation markers associated with MS are reported. In conclusion, low daily doses of flaxseed oil may improve clinical and metabolic parameters in middle-aged men without adequate treatment for metabolic syndrome.

Altered methylation of specific DNA loci in the liver of Bhmt-null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci.

Folate B12–dependent remethylation of homocysteine is important, but less is understood about the importance of the alternative betaine‐dependent methylation pathway—catalyzed by betaine‐homocysteine methyltransferase (BHMT)—for establishing and maintaining adequate DNA methylation across the genome. We studied C57Bl/6J Bhmt (betaine‐homocysteine methyltransferase)‐null mice at age 4, 12, 24, and 52 wk (N = 8) and observed elevation of S‐adenosylhomocysteine concentrations and development of preneoplastic foci in the liver (increased placental glutathione S‐transferase and cytokeratin 8–18 activity; starting at 12 wk). At 4 wk, we identified 63 differentially methylated CpGs (DMCs; false discovery rate < 5%) proximal to 81 genes (across 14 chromosomes), of which 18 were differentially expressed. Of these DMCs, 52% were located in one 15.5‐Mb locus on chromosome 13, which encompassed the Bhmt gene and defined a potentially sensitive region with mostly decreased methylation. Analyzing Hybrid Mouse Diversity Panel data, which consisted of 100 inbred strains of mice, we identified 97 DMCs that were affected by Bhmt genetic variation in the same region, with 7 overlapping those found in Bhmt‐null mice (P < 0.001). At all time points, we found a hypomethylated region mapping to Iqgap2 (IQ motif‐containing GTPase activating protein 2) and F2rl2 (proteinase‐activated receptor‐3), 2 genes that were also silenced and underexpressed, respectively.—Lupu, D. S., Orozco, L. D., Wang, Y., Cullen, J. M., Pellegrini, M., Zeisel, S. H. Altered methylation of specific DNA loci in the liver of Bhmt‐null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci. FASEB J. 31, 2090–2103 (2017). www.fasebj.org