Dietary fat quality, more than dietary fat quantity, impacts genome-wide DNA methylation patterns in Greek preadolescents
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ABSTRACT: The type and the amount of dietary fat have a significant influence on the metabolic pathways involved in the development of obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases. However, it is unknown to what extent this modulation is achieved through DNA methylation. We assessed the effects of cholesterol intake, the proportion of energy intake derived from fat, the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA), the ratio of monounsaturated fatty acids (MUFA) to SFA, and the ratio of (MUFA+PUFA) to SFA on genome-wide DNA methylation patterns in normal-weight and obese children. We determined the genome-wide methylation profile in blood of 69 Greek preadolescents (~10 y old), as well as their dietary intake for two consecutive weekdays and one weekend day. The methylation levels of four sites and a CpG island were significantly correlated with total fat intake. The methylation levels of 13 islands and 16 sites were significantly correlated with PUFA/SFA; of 35 islands and 158 sites with MUFA/SFA; and of 50 islands and 130 sites with (MUFA+PUFA)/SFA. We found significant gene enrichment in 26 pathways for PUFA/SFA, including the leptin pathway, and a significant enrichment in three pathways for (MUFA+PUFA)/SFA. Our results suggest that the quality, and to a lesser extent the quantity of fat intake, influences DNA methylation, including genes involved in metabolism. Thus, specific changes in DNA methylation may play an important role in the mechanisms involved in the physiological responses to different types of dietary fat. Bisulphite converted DNA from 22 boys were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2.Both obese and normal-weight indiviudals were included.
Project description:The type and the amount of dietary fat have a significant influence on the metabolic pathways involved in the development of obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases. However, it is unknown to what extent this modulation is achieved through DNA methylation. We assessed the effects of cholesterol intake, the proportion of energy intake derived from fat, the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA), the ratio of monounsaturated fatty acids (MUFA) to SFA, and the ratio of (MUFA+PUFA) to SFA on genome-wide DNA methylation patterns in normal-weight and obese children. We determined the genome-wide methylation profile in blood of 69 Greek preadolescents (~10 y old), as well as their dietary intake for two consecutive weekdays and one weekend day. The methylation levels of four sites and a CpG island were significantly correlated with total fat intake. The methylation levels of 13 islands and 16 sites were significantly correlated with PUFA/SFA; of 35 islands and 158 sites with MUFA/SFA; and of 50 islands and 130 sites with (MUFA+PUFA)/SFA. We found significant gene enrichment in 26 pathways for PUFA/SFA, including the leptin pathway, and a significant enrichment in three pathways for (MUFA+PUFA)/SFA. Our results suggest that the quality, and to a lesser extent the quantity of fat intake, influences DNA methylation, including genes involved in metabolism. Thus, specific changes in DNA methylation may play an important role in the mechanisms involved in the physiological responses to different types of dietary fat.
Project description:Obesity-related oesophageal adenocarcinoma (OAC), arising from Barret’s oesophagus (BO), incidence rates are rising coincident with high-fat diets. However, adipose tissue phenotype drives metabolic characteristics. Prior feeding studies demonstrated that obesogenic diets enriched in saturated fatty acids (SFA) induce a more adverse metabolic and pro-inflammatory adipose phenotype, compared to monounsaturated fatty acids (MUFA) enriched high-fat diets, despite equal obesity. We hypothesise that different fatty acids may alter the progression of BO to OAC, wherein SFA may be more pathogenic compared to MUFA. Proteomic analysis shows that SFA, not MUFA, increases fatty acid metabolism, oncogenic signalling, and mitochondrial respiratory chain to a greater extent in BO but not in OAC cells. Metabolic analysis validated proteomic findings to show mitochondrial dysfunction in BO but showed an increase in glycolysis in OAC following SFA treatment compared to MUFA. Additionally, it showed a decrease in mitochondrial ATP production following treatment of SFA in BO and OAC cells. Reduction of SFA intake may be beneficial as a supplementary treatment approach to manage and/or prevent OAC progression.
Project description:Dietary fat quality may influence skeletal muscle lipid handling and fat accumulation, thereby modulating insulin sensitivity. Objective: To examine acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA handling and postprandial insulin sensitivity in obese insulin resistant men. Design: In a single-blinded randomized crossover study, 10 insulin resistant men consumed three high-fat mixed-meals (2.6MJ). Meals were high in saturated FA (SFA), in monounsaturated FA (MUFA) or in polyunsaturated FA (PUFA). Fasting and postprandial skeletal muscle FA handling were examined by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and FFA in the circulation and [U-13C]-palmitate was added to the meal to label chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid metabolism and gene expression. Results: Insulin and glucose responses (AUC) after SFA meal were significantly higher compared with PUFA meal (p=0.003 and 0.028, respectively). Uptake of TAG-derived FA was significantly lower in the early postprandial phase after PUFA meal as compared with other meals (AUC60-120, p<0.001). The PUFA meal induced less transcriptional downregulation of oxidative pathways compared with other meals. The fractional synthetic rate was higher in DAG and PL fraction after MUFA and PUFA meal. Conclusion: Intake of a PUFA meal reduced TAG-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity and a tendency towards a higher muscle lipid turnover. These data suggest that the effects of replacement of SFA by PUFA may contribute to less muscle lipid uptake and may be therefore protective against the development of insulin resistance. Keywords: expression profiling by array randomized crossover dietary intervention study
Project description:Prolonged intervention studies investigating molecular metabolism are necessary for a deeper understanding of dietary effects on health. Here we provide mechanistic information about metabolic adaptation to fat-rich diets. Healthy men ingested saturated (SFA) or poly unsaturated (PUFA) fat-rich diets for six weeks during weight maintenance. Hyperinsulinemic clamps combined with leg balance technique revealed unchanged peripheral insulin sensitivity, independent of fatty acid type. Both diets increased fat oxidation potential in muscle. Hepatic insulin clearance increased, while glucose production, de novo lipogenesis and plasma triacylglycerol decreased. High fat intake changed the plasma proteome in immune-supporting direction and the gut microbiome displayed changes at taxonomical and functional level with PUFA. In mice, eucaloric feeding of human PUFA and SFA diets lowered hepatic triacylglycerol content compared to low-fat fed control mice, and induced adaptations in the liver supportive of decreased gluconeogenesis and lipogenesis. Intake of fat-rich diets thus induces extensive metabolic adaptations enabling disposition of dietary fat without metabolic complications.
Project description:Dietary fat quality may influence skeletal muscle lipid handling and fat accumulation, thereby modulating insulin sensitivity. Objective: To examine acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA handling and postprandial insulin sensitivity in obese insulin resistant men. Design: In a single-blinded randomized crossover study, 10 insulin resistant men consumed three high-fat mixed-meals (2.6MJ). Meals were high in saturated FA (SFA), in monounsaturated FA (MUFA) or in polyunsaturated FA (PUFA). Fasting and postprandial skeletal muscle FA handling were examined by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and FFA in the circulation and [U-13C]-palmitate was added to the meal to label chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid metabolism and gene expression. Results: Insulin and glucose responses (AUC) after SFA meal were significantly higher compared with PUFA meal (p=0.003 and 0.028, respectively). Uptake of TAG-derived FA was significantly lower in the early postprandial phase after PUFA meal as compared with other meals (AUC60-120, p<0.001). The PUFA meal induced less transcriptional downregulation of oxidative pathways compared with other meals. The fractional synthetic rate was higher in DAG and PL fraction after MUFA and PUFA meal. Conclusion: Intake of a PUFA meal reduced TAG-derived skeletal muscle FA uptake, which was accompanied by higher postprandial insulin sensitivity and a tendency towards a higher muscle lipid turnover. These data suggest that the effects of replacement of SFA by PUFA may contribute to less muscle lipid uptake and may be therefore protective against the development of insulin resistance. Keywords: expression profiling by array
Project description:Solid evidence indicates that intake of marine n-3 fatty acids lower serum triglycerides, and that replacing saturated fatty acids (SFA) with polyunsaturated fatty acids (PUFA) reduces plasma total cholesterol and LDL-cholesterol. The molecular mechanisms underlying these health beneficial effects are however not completely elucidated. The aim of this study was to investigate the expression of genes related to lipid metabolism in peripheral blood mononuclear cells (PBMC) depending on the plasma levels of n-6 and n-3 fatty acids and the SFA to PUFA ratio.
Project description:In a randomized controlled dietary intervention study, we compared a diet enriched in polyunsaturated fatty acids (PUFA) with a diet enriched in saturated fatty acids (SFA) for influence on abdominal subcutaneous adipose tissue gene expression. We studied young lean adults; 11 women and 25 men. There was no significant difference in age, BMI, or gene expression between the PUFA and SFA groups before the intervention. The intervention lasted for seven weeks. We calculated for each gene the absolute difference in gene expression after vs. before intervention (deltas), and compared the deltas between the PUFA and SFA group using SAM. 12 genes were significantly differentially regulated by the two diets with a FDR of 25%. These include metabolic and adipokine genes. In conclusion, dietary fatty acids have a modest influence on white adipose tissue gene expression.
Project description:In a randomized controlled dietary intervention study, we compared a diet enriched in polyunsaturated fatty acids (PUFA) with a diet enriched in saturated fatty acids (SFA) for influence on abdominal subcutaneous adipose tissue gene expression. We studied young lean adults; 11 women and 25 men. There was no significant difference in age, BMI, or gene expression between the PUFA and SFA groups before the intervention. The intervention lasted for seven weeks. We calculated for each gene the absolute difference in gene expression after vs. before intervention (deltas), and compared the deltas between the PUFA and SFA group using SAM. 12 genes were significantly differentially regulated by the two diets with a FDR of 25%. These include metabolic and adipokine genes. In conclusion, dietary fatty acids have a modest influence on white adipose tissue gene expression. Abdominal subcutaneous adipose needle biopsies were obtained from young adults before (W0) and after completion (W7) of the dietary intervention. From the biopsies we extracted RNA. From total RNA we prepared and hybridised biotinylated complementary RNA to GeneChip Human Gene 1.1 ST Arrays (Affymetrix, Inc., Santa Clara, CA), and then washed, stained and scanned the slides using standardised protocols (Affymetrix, Inc.). Signicance analysis of microarrays (SAM) was use to compare the difference in gene expression between groups.
Project description:Saturated fatty acids (SFA) are widely thought to induce inflammation in adipose tissue (AT), while monounsaturated fatty acids (MUFA) are purported to have the opposite effect; however, it is unclear if individual SFA and MUFA behave similarly. Our goal was to examine adipocyte transcriptional networks regulated by individual SFA (palmitic acid, PA; stearic acid, SA) and MUFA (palmitoleic acid, PMA; oleic acid, OA). Global gene expression was examined in differentiated preadipocytes treated with either 250 μM PA, SA, PMA, or OA for 48 hrs. Individual fatty acid treatments had significant effects on adipocyte gene expression. Functional analyses revealed that PA induced the TLR signalling pathway, while PMA had the opposite effect. SA and OA had similar effects, with increases in key metabolic pathways including mTOR and PPAR signalling, and a reduction in TLR signalling. Ccl5 was validated as a candidate gene that may mediate the differential inflammatory effects of SFA and MUFA in AT. Individual SFA and MUFA trigger distinct transcriptional responses in differentiated preadipocytes, with inflammatory and metabolic pathways particularly sensitive to these fatty acids.
Project description:Early perturbations in vascular health can be detected by imposing subjects to a high fat (HF) challenge and measure response capacity. Subtle responses can be determined by assessment of whole-genome transcriptional changes. We aimed to magnify differences in health by comparing gene-expression changes in peripheral blood mononuclear cells (PBMCs) towards a high MUFA or SFA challenge between subjects with different cardiovascular disease risk profiles and to identify fatty-acid specific gene-expression pathways. METHODS AND RESULTS: In a cross-over study, 17 lean and 15 obese men (50-70y) received two 95g fat shakes, high in SFAs or MUFAs. PBMC gene-expression profiles were assessed fasted and 4h postprandially. Comparisons were made between groups and shakes. During fasting, 294 genes were significantly different expressed between lean and obese. The challenge increased differences to 607 genes after SFA and 2516 genes after MUFA. In both groups, SFA decreased expression of cholesterol biosynthesis and uptake genes and increased cholesterol efflux genes. MUFA increased inflammatory genes and PPAR? targets involved in ?-oxidation. CONCLUSION: Based upon gene-expression changes, we conclude that a HF challenge magnifies differences in health, especially after MUFA. Our findings also demonstrate how SFAs and MUFAs exert distinct effects on lipid handling pathways in immune cells. In a double-blind cross-over study, 17 lean and 15 obese men (aged 50-70y) received two high-fat milkshakes containing 95g fat, either high in saturated (SFA) or monounsaturated (MUFA) fatty acids. PBMC gene expression profiles were determined before and 4h after shake consumption.