Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

Abstract

We have previously shown that blood global DNA methylation (DNAm) differs between postprandial state (PS) and fasting state (FS) and is associated with BMI and polyunsaturated fatty acid (PUFA) (negatively and positively, respectively) in 12 metabolically healthy adult Mexican men (AMM cohort) equally distributed among conventional BMI classes. Here, we detailed those associations at CpG dinucleotide level by exploiting the Infinium methylation EPIC array (Illumina). We sought differentially methylated CpG (dmCpG) that were (1) associated with BMI (BMI-dmCpG) and/or fatty acids (FA) (FA-dmCpG) in FS or PS and (2) different across FS and PS within a BMI class. BMI-dmCpG and FA-dmCpG were more numerous in FS compared to PS and largely prandial state-specific. For saturated and monounsaturated FA, dmCpG overlap was higher across than within the respective saturation group. Several BMI- and FA-dmCpG mapped to genes involved in metabolic disease and in some cases matched published experimental data sets. Notably, SETDB1 and MTHFS promoter dmCpG could explain the previously observed associations between global DNAm, PUFA content, and BMI in FS. Surprisingly, overlap between BMI-dmCpG and FA-dmCpG was limited and the respective dmCpG were differentially distributed across functional genomic elements. BMI-dmCpG showed the highest overlap with dmCpG of the saturated FA palmitate, monounsaturated C20:1 and PUFA C20:2. Of these, selected promoter BMI-dmCpG showed opposite associations with palmitate compared to C20:1 and C20:2. As for the comparison between FS and PS within BMI classes, dmCpG were strikingly more abundant and variably methylated in overweight relative to normoweight or obese subjects (∼70–139-fold, respectively). Overweight-associated dmCpG-hosting genes were significantly enriched in targets for E47, SREBP1, and RREB1 transcription factors, which are known players in obesity and lipid homeostasis, but none overlapped with BMI-dmCpG. We show for the first time that the association of BMI and FA with methylation of disease-related genes is distinct in FS and PS and that limited overlap exists between BMI- and FA-dmCpG within and across prandial states. Our study also identifies a transcriptional regulation circuitry in overweight that might contribute to adaptation to that condition or to transition to obesity. Further work is necessary to define the pathophysiological implications of these findings.

Interrelated but Not Time-Aligned Response in Myogenic Regulatory Factors Demethylation and mRNA Expression after Divergent Exercise Bouts

“…Despite this, we suggest that future studies be conducted with an experimental design that makes it possible to investigate the influence of duration and energy demand on MRF epigenetic regulation. Also, some of the aforementioned differences between our data and previous results could be explained by the control standard meal we provided in our experimental design to avoid possible fasting effects on DNA methylation and mRNA expression (24–26). Moreover, we acknowledge that we only analyzed DNA methylation in one specific region of each target gene, raising the possibility that other regions within the genes may have different sensitivities to exercise than those reported in the current investigation.…”

“…On the evening before an experimental testing session, a standard meal (3 g of carbohydrate, 0.5 g of protein, and 0.3 g of fat per kilogram of body mass [23]) was provided to the participants as the last meal of the day. Three hours before each muscle biopsy, participants were provided a small meal (60 g of CHO, 10 g of proteins, and 23.8 g of fat, total energy 2001 kJ) to avoid possible fasting effects on DNA methylation and mRNA expression (24)(25)(26).…”

The Metabolic Signature of In Vitro Produced Bovine Embryos Helps Predict Pregnancy and Birth after Embryo Transfer

“…An excess of palmitic and other FAs impacts DNA methylation, therefore leading to epigenetic alteration, as observed within different cell types [ 56 ], and in fasting to post-prandial transitions in obese humans [ 57 , 58 ]. These events are conceptually similar to the dynamic reprogramming during embryonic development, by which environmental stimuli (including assisted reproductive technologies) lead to acquisition of a stable, modified genotype later in life [ 59 ] and, in this case, loss of pregnancy competence.…”

Liver saturated fat content associates with hepatic DNA methylation in obese individuals

“…We found palmitic and stearic acid to be the most correlated more often with DNA methylation of the CpGs linked with SFA. Earlier studies in humans and humanderived cells have found that both palmitic and stearic acids actively interact with the epigenome [25,27,29,60]. For instance, excess palmitic and stearic acid is known to induce inflammation and metabolic dysregulations in various cell models (including primary murine hepatocytes) along with alterations in histone acetylation and DNA methylation [61][62][63][64].…”