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

BACKGROUND: Accumulation of saturated fatty acids (SFAs) in the liver is known to induce hepatic steatosis and inflammation causing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Although SFAs have been shown to affect the epigenome in whole blood, pancreatic islets, and adipose tissue in humans, and genome-wide DNA methylation studies have linked epigenetic changes to NAFLD and NASH, studies focusing on the association of SFAs and DNA methylation in human liver are missing. We, therefore, investigated whether human liver SFA content associates with DNA methylation and tested if SFA-linked alterations in DNA methylation associate with NAFLD-related clinical phenotypes in obese individuals. RESULTS: We identified DNA methylation (Infinium HumanMethylation450 BeadChip) of 3169 CpGs to be associated with liver total SFA content (q-value < 0.05) measured using proton NMR spectroscopy in participants of the Kuopio Obesity Surgery Study (n = 51; mean ± SD:49.3 ± 8.5 years old; BMI:43.7 ± 6.2 kg/m2). Of these 3169 sites, 797 overlapped with previously published NASH-associated CpGs (NASH-SFA), while 2372 CpGs were exclusively associated with SFA (Only-SFA). The corresponding annotated genes of these only-SFA CpGs were found to be enriched in pathways linked to satiety and hunger. Among the 54 genes mapping to these enriched pathways, DNA methylation of CpGs mapping to PRKCA and TSPO correlated with their own mRNA expression (HumanHT-12 Expression BeadChip). In addition, DNA methylation of another ten of these CpGs correlated with the mRNA expression of their neighboring genes (p value < 0.05). The proportion of CpGs demonstrating a correlation of DNA methylation with plasma glucose was higher in NASH-SFA and only-SFA groups, while the proportion of significant correlations with plasma insulin was higher in only-NASH and NASH-SFA groups as compared to all CpGs on the Illumina 450 K array (Illumina, San Diego, CA, USA). CONCLUSIONS: Our results suggest that one of the mechanisms how SFA could contribute to metabolic dysregulation in NAFLD is at the level of DNA methylation. We further propose that liver SFA-related DNA methylation profile may contribute more to hyperglycemia, while insulin-related methylation profile is more linked to NAFLD or NASH. Further research is needed to elucidate the molecular mechanisms behind these observations.

The FADS1 rs174550 Genotype Modifies the n-3 and n-6 PUFA and Lipid Mediator Responses to a High Alpha-Linolenic Acid and High Linoleic Acid Diets.

SCOPE: The fatty acid composition of plasma lipids, which is associated with biomarkers and risk of non-communicable diseases, is regulated by dietary polyunsaturated fatty acids (PUFAs) and variants of fatty acid desaturase (FADS). We investigated the interactions between dietary PUFAs and FADS1 rs174550 variant. METHODS AND RESULTS: Participants (n = 118), homozygous for FADS1 rs174550 variant (TT and CC) followed a high alpha-linolenic acid (ALA, 5 percent of energy (E-%)) or a high linoleic acid (LA, 10 E-%) diet during an 8-week randomized controlled intervention. Fatty acid composition of plasma lipids and PUFA-derived lipid mediators were quantified by gas and liquid chromatography mass spectrometry, respectively. The high-LA diet increased the concentration of plasma LA, but not its lipid mediators. The concentration of plasma arachidonic acid decreased in carriers of CC and remained unchanged in the TT genotype. The high-ALA diet increased the concentration of plasma ALA and its cytochrome P450-derived epoxides and dihydroxys, and cyclooxygenase-derived monohydroxys. Concentrations of plasma eicosapentaenoic acid and its mono- and dihydroxys increased only in TT genotype carriers. CONCLUSIONS: These findings suggest the potential for genotype-based recommendations for PUFA consumption, resulting in modulation of bioactive lipid mediators which can exert beneficial effects in maintaining health.

The FADS1 genotypes modify the effect of linoleic acid-enriched diet on adipose tissue inflammation via pro-inflammatory eicosanoid metabolism.

PURPOSE: Fatty acid desaturase (FADS) variants associate with fatty acid (FA) and adipose tissue (AT) metabolism and inflammation. Thus, the role of FADS1 variants in the regulation of dietary linoleic acid (LA)-induced effects on AT inflammation was investigated. METHODS: Subjects homozygotes for the TT and CC genotypes of the FADS1-rs174550 (TT, n = 25 and CC, n = 28) or -rs174547 (TT, n = 42 and CC, n = 28), were either recruited from the METabolic Syndrome In Men cohort to participate in an intervention with LA-enriched diet (FADSDIET) or from the Kuopio Obesity Surgery (KOBS) study. GC and LC-MS for plasma FA proportions and eicosanoid concentrations and AT gene expression for AT inflammatory score (AT-InSc) was determined. RESULTS: We observed a diet-genotype interaction between LA-enriched diet and AT-InSc in the FADSDIET. In the KOBS study, interleukin (IL)1 beta mRNA expression in AT was increased in subjects with the TT genotype and highest LA proportion. In the FADSDIET, n-6/LA proportions correlated positively with AT-InSc in those with the TT genotype but not with the CC genotype after LA-enriched diet. Specifically, LA- and AA-derived pro-inflammatory eicosanoids related to CYP450/sEH-pathways correlated positively with AT-InSc in those with the TT genotype, whereas in those with the CC genotype, the negative correlations between pro-inflammatory eicosanoids and AT-InSc related to COX/LOX-pathways. CONCLUSIONS: LA-enriched diet increases inflammatory AT gene expression in subjects with the TT genotype, while CC genotype could play a protective role against LA-induced AT inflammation. Overall, the FADS1 variant could modify the dietary LA-induced effects on AT inflammation through the differential biosynthesis of AA-derived eicosanoids.

The FADS1 Genotype Modifies Metabolic Responses to the Linoleic Acid and Alpha-linolenic Acid Containing Plant Oils-Genotype Based Randomized Trial FADSDIET2.

SCOPE: The article investigates the FADS1 rs174550 genotype interaction with dietary intakes of high linoleic acid (LA) and high alpha-linolenic acid (ALA) on the response of fatty acid composition of plasma phospholipids (PLs), and of markers of low-grade inflammation and glucose-insulin homeostasis. METHODS AND RESULTS: One-hundred thirty homozygotes men for FADS1 rs174550 SNP (TT and CC genotypes) were randomized to an 8-week intervention with either LA- or ALA-enriched diet (13 E% PUFA). The source of LA and ALA are 30-50 mL of sunflower oil (SFO, 62-63% LA) and Camelina sativa oil (CSO, 30- are randomized to an 35% ALA), respectively. In the SFO arm, there is a significant genotype x diet interaction for the proportion of arachidonic acid in plasma phospholipids (p < 0.001), disposition index (DI30 ) (p = 0.039), and for serum high-sensitive c-reactive protein (hs-CRP, p = 0.029) after excluding the participants with hs-CRP concentration of >10 mg L-1 and users of statins or anti-inflammatory therapy. In the CSO arm, there are significant genotype x diet interactions for n-3 polyunsaturated fatty acids, but not for the clinical characteristics. CONCLUSIONS: The FADS1 genotype modifies the response to high PUFA diets, especially to high-LA diet. These findings suggest that approaches considering FADS variation may be useful in personalized dietary counseling.

The effects of a 2-year physical activity and dietary intervention on plasma lipid concentrations in children: the PANIC Study.

PURPOSE: We studied the effects of a physical activity and dietary intervention on plasma lipids in a general population of children. We also investigated how lifestyle changes contributed to the intervention effects. METHODS: We carried out a 2-year controlled, non-randomized lifestyle intervention study among 504 mainly prepubertal children aged 6-9 years at baseline. We assigned 306 children to the intervention group and 198 children to the control group. We assessed plasma concentrations of total, LDL, HDL, and VLDL cholesterol, triglycerides, HDL triglycerides, and VLDL triglycerides. We evaluated the consumption of foods using 4-day food records and physical activity using a movement and heart rate sensor. We analyzed data using linear mixed-effect models adjusted for age at baseline, sex, and pubertal stage at both time points. Furthermore, specific lifestyle variables were entered in these models. RESULTS: Plasma LDL cholesterol decreased in the intervention group but did not change in the control group ( - 0.05 vs. 0.00 mmol/L, regression coefficient (ß) = - 0.0385, p = 0.040 for group*time interaction). This effect was mainly explained by the changes in the consumption of high-fat vegetable oil-based spreads (ß = - 0.0203, + 47% change in ß) and butter-based spreads (ß = - 0.0294, + 30% change in ß), moderate-to-vigorous physical activity (ß = - 0.0268, + 30% change in ß), light physical activity (ß = - 0.0274, + 29% change in ß) and sedentary time (ß = - 0.0270, + 30% change in ß). The intervention had no effect on other plasma lipids. CONCLUSION: Lifestyle intervention resulted a small decrease in plasma LDL cholesterol concentration in children. The effect was explained by changes in quality and quantity of dietary fat and physical activity. CLINICAL TRIAL REGISTRY NUMBER: NCT01803776, ClinicalTrials.gov.

Inflammatory response to dietary linoleic acid depends on FADS1 genotype.

Background: The health benefits of substituting dietary polyunsaturated fatty acids (PUFAs) for saturated fatty acids are well known. However, limited information exists on how the response to dietary intake of linoleic acid (LA; 18:2n-6) is modified by polymorphisms in the fatty acid desaturase (FADS) gene cluster. Objectives: The aim of the current study was to test the hypothesis that the FADS1 rs174550 genotype modifies the effect of dietary LA intake on the fatty acid composition of plasma lipids, fasting glucose, and high-sensitivity C-reactive protein (hsCRP). Methods: Associations were investigated between genotype, plasma PUFAs, fasting glucose, and hsCRP concentrations in the cross-sectional, population-based Metabolic Syndrome in Men cohort (n = 1337). In addition, 62 healthy men from the cohort who were homozygotes for the TT or CC genotype of the FADS1 rs174550 were recruited to a 4-wk intervention (FADSDIET) with an LA-enriched diet. The fatty acid composition of plasma PUFAs and concentrations of plasma fasting glucose, serum hsCRP, and plasma lipid mediators (eicosanoids and related analogs) were measured at the beginning and end of the 4-wk intervention period. Results: In the FADSDIET trial, the plasma LA proportion increased in both genotype groups in response to an LA-enriched diet. Responses in concentrations of serum hsCRP and plasma fasting glucose and the proportion of arachidonic acid (20:4n-6) in plasma phospholipids and cholesteryl esters differed between genotype groups (interaction of diet × genotype, P < 0.05). In TT homozygous subjects, plasma eicosanoid concentrations correlated with the arachidonic acid proportion in plasma and with hsCRP (r = 0.4-0.7, P < 0.05), whereas in the CC genotype there were no correlations. Conclusions: Our findings show that the FADS1 genotype modifies metabolic responses to dietary LA. The emerging concept that personalized dietary counseling should be modified by the FADS1 genotype needs to be tested in larger randomized trials. The study was registered at clinicaltrials.gov as NCT02543216.

Associations of Dehydroepiandrosterone Sulfate With Cardiometabolic Risk Factors in Prepubertal Children.

Context: Premature adrenarche (PA) has been associated with overweight and insulin resistance, but the associations of serum dehydroepiandrosterone sulfate (DHEAS) concentration with other cardiometabolic risk factors are uncertain. Objective: To examine the associations of serum DHEAS concentration with several cardiometabolic risk factors in children. Design: Cross-sectional data from the Physical Activity and Nutrition in Children Study. Participants: Population sample of 207 girls and 225 boys aged 7.6 ± 0.4 years. Main Outcome Measures: Cardiometabolic risk factors by serum DHEAS concentration. Results: DHEAS correlated positively with body mass index standard deviation score, body fat percentage, lean body mass, high-sensitivity C-reactive protein (hs-CRP), and alanine aminotransferase (ALT) when adjusted for age and sex. The associations of DHEAS with hs-CRP and ALT disappeared when adjusted also for body fat percentage. When further adjusted for birth weight SD score, DHEAS correlated negatively with low-density lipoprotein (LDL) cholesterol and LDL/high-density lipoprotein (HDL) cholesterol ratio. LDL cholesterol was lower in children with DHEAS ≥40 µg/dL than in those with DHEAS <40 µg/dL, adjusted for age, sex, and body fat percentage (86.5 vs 92.3 mg/dL, P = 0.029). This association strengthened after further adjustment for birth weight SD score (85.3 vs 92.3 mg/dL, P = 0.012). Conclusion: Higher DHEAS is not associated with an increased cardiometabolic risk in prepubertal children. Instead, it may be protective, evidenced by an association with lower LDL cholesterol and LDL/HDL cholesterol ratio. The increased cardiometabolic risk in PA shown in many studies may be due to low birth weight and childhood overweight associated with PA.

Interorgan cross talk between fatty acid metabolism, tissue inflammation, and FADS2 genotype in humans with obesity.

OBJECTIVE: Fatty acid (FA) composition affects obesity-associated low-grade inflammation. It has been shown that the fatty acid desaturase (FADS) 2 gene polymorphism associates with FA metabolism and adipose tissue (AT) inflammation. This study aimed to investigate the relationship between FA metabolism and inflammation in different tissues and the possible interorgan cross talk. METHODS: Cross-sectional baseline data from 155 individuals with obesity (both male and female) participating in the Roux-en-Y gastric bypass operation in the ongoing Kuopio Obesity Surgery Study were used. Gas chromatograph for FA composition, liver histology, and targeted RNA expression for gene expression profile were performed. RESULTS: It was demonstrated that the saturated fatty acid (SFA) proportion in AT correlated positively with inflammation in subcutaneous AT (SAT) and visceral AT (VAT) but not in the liver, while the monounsaturated fatty acid (MUFA) proportion in SAT and VAT correlated negatively with AT inflammation. Notably, there was a positive correlation between AT n-6 polyunsaturated fatty acids (PUFAs), but not AT SFAs or MUFAs, and liver inflammation. This correlation was modified by the FADS2 genotype. CONCLUSIONS: The AT FA profile relates with AT inflammation. Additionally, there seems to be a complex interaction, partly regulated by the FADS2 genotype, regulating the interaction between FAs in AT and liver inflammation.

Effect of a 2-y dietary and physical activity intervention on plasma fatty acid composition and estimated desaturase and elongase activities in children: the Physical Activity and Nutrition in Children Study.

BACKGROUND: Evidence on the effects of lifestyle interventions on plasma fatty acid composition in children is limited. OBJECTIVE: We investigated the effects of a dietary and physical activity intervention on plasma fatty acid composition of cholesteryl esters (CEs) and phospholipids and estimated desaturase and elongase activities in children. DESIGN: We conducted a 2-y controlled dietary and physical activity intervention based on Finnish nutrition and physical activity recommendations in a population sample of 506 children aged 6-8 y. We assessed plasma fatty acid composition by gas chromatography and estimated desaturase and elongase activities as the ratio of product fatty acids to precursor fatty acids. We analyzed data by using linear mixed models adjusted for age and sex. RESULTS: The proportion of total polyunsaturated fatty acids (PUFAs) in CEs tended to increase in the intervention group compared with the control group (P = 0.007 for group × time interaction). The proportion of total PUFAs in phospholipids (P = 0.019 for group × time interaction) and the proportion of linoleic acid in CEs (P = 0.038 for group × time interaction) decreased in the control group. The proportion of α-linolenic acid in CEs (P < 0.001 for group × time interaction) increased and in phospholipids (P = 0.015 for group × time interaction) tended to increase in the intervention group. The proportion of stearic acid in CEs decreased in the intervention group (P = 0.001 for group × time interaction). The proportion of oleic acid in CEs (P = 0.002 for group × time interaction) increased and in phospholipids (P = 0.023 for group × time interaction) tended to increase in the control group. Estimated elongase activity in CEs decreased in the control group (P = 0.050 for group × time interaction). Intervention had no effect on estimated desaturase activities. CONCLUSIONS: Dietary and physical activity intervention had a beneficial effect on plasma fatty acid composition in children by preventing the decrease in the proportion of total PUFAs and linoleic acid and by increasing the proportion of α-linolenic acid. This study was registered at clinicaltrials.gov as NCT01803776.

Fatty acid metabolism is altered in non-alcoholic steatohepatitis independent of obesity.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is associated with changes in fatty acid (FA) metabolism. However, specific changes in metabolism and hepatic mRNA expression related to NASH independent of simple steatosis, obesity and diet are unknown. METHODS: Liver histology, serum and liver FA composition and estimated enzyme activities based on the FA ratios in cholesteryl esters and triglycerides were assessed in 92 obese participants of the Kuopio Obesity Surgery Study (KOBS) divided to those with normal liver, steatosis or NASH (30 men and 62 women, age 46.8±9.5years (mean±SD), BMI 44.2±6.2kg/m(2)). Plasma FA composition was also investigated in the Metabolic Syndrome in Men (METSIM) Study (n=769), in which serum alanine aminotransferase (ALT) was used as a marker of liver disease. RESULTS: Obese individuals with NASH had higher activity of estimated activities of delta-6 desaturase (D6D, p<0.002) and stearoyl-CoA desaturase 1 (SCD1, p<0.002) and lower activity of delta-5 desaturase (D5D, p<0.002) when compared to individuals with normal liver. Estimated activities of D5D, D6D and SCD1 correlated positively between liver and serum indicating that serum estimates reflected liver metabolism. Accordingly, NASH was associated with higher hepatic mRNA expression of corresponding genes FADS1, FADS2 and SCD. Finally, differences in FA metabolism that associated with NASH in obese individuals were also associated with high ALT in the METSIM Study. CONCLUSIONS: We demonstrated alterations in FA metabolism and endogenous desaturase activities that associate with NASH, independent of obesity and diet. This suggests that changes in endogenous FA metabolism are related to NASH and that they may contribute to the progression of the disease.

Cross-sectional associations of plasma fatty acid composition and estimated desaturase and elongase activities with cardiometabolic risk in Finnish children--The PANIC study.

BACKGROUND: Knowledge on the association of plasma fatty acid (FA) composition in triacylglycerol (TG) and phospholipid (PL) fractions with cardiometabolic risk in population-based samples of children is lacking. OBJECTIVE: We investigated the associations of proportions of FA in plasma TG and PL fractions as well as estimated desaturase and elongase activities with cardiometabolic risk in a population sample of 384 children aged 6-8 years. METHODS: Plasma FA composition was analyzed by gas chromatography. Desaturase and elongase activities were estimated as product-to-precursor FA ratios. Cardiometabolic risk was assessed using a continuous cardiometabolic risk score (CRS) variable. RESULTS: Higher proportions of myristic and palmitoleic acids in plasma TG and PL were associated with a higher CRS. A lower proportion of linoleic acid in plasma TG was related to a higher CRS. Estimated stearoyl-CoA-desaturase and Δ6-desaturase activities in plasma TG and PL were directly associated with CRS, whereas estimated elongase activity in plasma TG and PL was inversely related to CRS. CONCLUSIONS: Greater proportions of myristic and palmitoleic acids and a smaller proportion of linoleic acid in plasma, as well as higher estimated stearoyl-CoA-desaturase and Δ6-desaturase activities and a lower estimated elongase activity, are associated with cardiometabolic risk factors among children. These findings reinforce the evidence that FA metabolism is closely associated with cardiometabolic risk, starting already from childhood.

FADS2 genotype regulates delta-6 desaturase activity and inflammation in human adipose tissue.

Obesity is associated with disturbed lipid metabolism and low-grade inflammation in tissues. The aim of this study was to investigate the association between FA metabolism and adipose tissue (AT) inflammation in the Kuopio Obesity Surgery study. We investigated the association of surgery-induced weight loss and FA desaturase (FADS)1/2 genotypes with serum and AT FA profile and with AT inflammation, measured as interleukin (IL)-1ß and NFκB pathway gene expression, in order to find potential gene-environment interactions. We demonstrated an association between serum levels of saturated and polyunsaturated n-6 FAs, and estimated enzyme activities of FADS1/2 genes with IL-1ß expression in AT both at baseline and at follow-up. Variation in the FADS1/2 genes associated with IL-1ß and NFκB pathway gene expression in SAT after weight reduction, but not at baseline. In addition, the FA composition in subcutaneous and visceral fat correlated with serum FAs, and the associations between serum PUFAs and estimated D6D enzyme activity with AT inflammation were also replicated with corresponding AT FAs and AT inflammation. We conclude that the polymorphism in FADS1/2 genes associates with FA metabolism and AT inflammation, leading to an interaction between weight loss and FADS1/2 genes in the regulation of AT inflammation.

Gene-diet interaction of a common FADS1 variant with marine polyunsaturated fatty acids for fatty acid composition in plasma and erythrocytes among men.

SCOPE: Limited information exists on how the relationship between dietary intake of fat and fatty acids in erythrocytes and plasma is modulated by polymorphisms in the FADS gene cluster. We examined gene-diet interaction of total marine PUFA intake with a known gene encoding Δ-5 desaturase enzyme (FADS1) variant (rs174550) for fatty acids in erythrocyte membranes and plasma phospholipids (PL), cholesteryl esters (CE), and triglycerides (TG). METHODS AND RESULTS: In this cross-sectional study, fatty acid compositions were measured using GC, and total intake of polyunsaturated fat from fish and fish oil was estimated using a food frequency questionnaire in a subsample (n = 962) of the Metabolic Syndrome in Men Study. We found nominally significant gene-diet interactions for eicosapentaenoic acid (EPA, 20:5n-3) in erythrocytes (pinteraction = 0.032) and for EPA in plasma PL (pinteraction = 0.062), CE (pinteraction = 0.035), and TG (pinteraction = 0.035), as well as for docosapentaenoic acid (22:5n-3) in PL (pinteraction = 0.007). After excluding omega-3 supplement users, we found a significant gene-diet interaction for EPA in erythrocytes (pinteraction < 0.003). In a separate cohort of the Kuopio Obesity Surgery Study, the same locus was strongly associated with hepatic mRNA expression of FADS1 (p = 1.5 × 10(-10) ). CONCLUSION: FADS1 variants may modulate the relationship between marine fatty acid intake and circulating levels of long-chain omega-3 fatty acids.

Dietary polyunsaturated fatty acids and the Pro12Ala polymorphisms of PPARG regulate serum lipids through divergent pathways: a randomized crossover clinical trial.

Human and animal studies suggest an interaction between the Pro12Ala polymorphism of PPARG and dietary fat. In this randomized crossover clinical trial, we investigated whether subjects with the Pro12Pro and Ala12Ala genotypes of PPARG respond differently to a diet supplemented with high saturated (SAFA) or polyunsaturated fatty acid (PUFA).We recruited non-diabetic men from a population-based METSIM study (including 10,197 men) to obtain men with the Ala12Ala and the Pro12Pro genotypes matched for age and body mass index. Seventeen men with the Pro12Pro genotype and 14 with the Ala12Ala genotype were randomized to both a PUFA diet and a SAFA diet for 8 weeks in a crossover setting. Serum lipids and adipose tissue mRNA expression were measured during the diet intervention. At baseline, subjects with the Ala12Ala genotype had higher levels of HDL cholesterol and lower levels of LDL cholesterol, total triglycerides, and apolipoprotein B compared to those subjects with the Pro12Pro genotype (P < 0.05, FDR < 0.1). The Ala12Ala genotype also associated with higher mRNA expression of PPARG2, LPIN1, and SREBP-1c compared to participants with the Pro12Pro genotype (FDR < 0.001). On the other hand, PUFA diet resulted in lower levels of fasting glucose, total cholesterol, total triglycerides, and apolipoprotein B (P < 0.05, FDR < 0.1) but did not affect PPARG2 mRNA expression in adipose tissue. We conclude that individuals with the Pro12Pro genotype, with higher triglyceride levels at baseline, are more likely to benefit from the PUFA diet. However, the beneficial effects of dietary PUFA and the Ala12Ala genotype of PPARG on serum lipids are mediated through divergent mechanisms.

Plasma fatty acids as predictors of glycaemia and type 2 diabetes.

AIMS/HYPOTHESIS: Our aim was to investigate the fasting proportions of fatty acids and estimated desaturase and elongase activities in three different lipid fractions in plasma, phospholipids (PLs), cholesteryl esters (CEs) and triacylglycerols (TGs), as predictors for the worsening of glycaemia (area under the glucose curve in an OGTT [glucose AUC]) and incident type 2 diabetes in a 5.9 year follow-up of the Metabolic Syndrome in Men population-based cohort. METHODS: Fatty acid proportions were measured in plasma PL, CE and TG fractions in 1,364 Finnish men aged 45-68 years at baseline. The prospective follow-up study included only men who were non-diabetic at baseline and had data available at follow-up (n = 1,302). A total of 71 participants developed new type 2 diabetes during follow-up. RESULTS: After adjusting for confounding factors, total saturated fatty acids, palmitoleic acid (16:1n-7), dihomo-γ-linolenic acid (20:3n-6) and estimated stearoyl-CoA desaturase 1 and Δ(6)-desaturase (D6D) enzyme activities significantly predicted the worsening of glycaemia whereas total polyunsaturated fatty acid, linoleic acid (18:2n-6) and elongase activity predicted a decrease in the glucose AUC. Estimated D6D activity and dihomo-γ-linolenic acid (20:3n-6) were associated with an increased risk of incident type 2 diabetes. Results were consistent across the three different lipid fractions. However, fatty acid proportions in the PL and CE fractions were stronger predictors for glycaemia and incident type 2 diabetes compared with fatty acid proportions in the TG fraction. CONCLUSIONS/INTERPRETATION: Selected fatty acid proportions of plasma lipid fractions and their ratios, which reflect desaturase and elongase enzyme activities, may be good biomarkers for the worsening of glycaemia and incident type 2 diabetes.

Physical activity and sedentary behaviour in relation to cardiometabolic risk in children: cross-sectional findings from the Physical Activity and Nutrition in Children (PANIC) Study.

BACKGROUND: Lower levels of physical activity (PA) and sedentary behaviour (SB) have been associated with increased cardiometabolic risk among children. However, little is known about the independent and combined associations of PA and SB as well as different types of these behaviours with cardiometabolic risk in children. We therefore investigated these relationships among children. METHODS: The subjects were a population sample of 468 children 6-8 years of age. PA and SB were assessed by a questionnaire administered by parents and validated by a monitor combining heart rate and accelerometry measurements. We assessed body fat percentage, waist circumference, blood glucose, serum insulin, plasma lipids and lipoproteins and blood pressure and calculated a cardiometabolic risk score using population-specific Z-scores and a formula waist circumference + insulin + glucose + triglycerides - HDL cholesterol + mean of systolic and diastolic blood pressure. We analysed data using multivariate linear regression models. RESULTS: Total PA was inversely associated with the cardiometabolic risk score (ß = -0.135, p = 0.004), body fat percentage (ß = -0.155, p < 0.001), insulin (ß = -0.099, p = 0.034), triglycerides (ß = -0.166, p < 0.001), VLDL triglycerides (ß = -0.230, p < 0.001), VLDL cholesterol (ß = -0.168, p = 0.001), LDL cholesterol (ß = -0.094, p = 0.046) and HDL triglycerides (ß = -0.149, p = 0.004) and directly related to HDL cholesterol (ß = 0.144, p = 0.002) adjusted for age and gender. Unstructured PA was inversely associated with the cardiometabolic risk score (ß = -0.123, p = 0.010), body fat percentage (ß = -0.099, p = 0.027), insulin (ß = -0.108, p = 0.021), triglycerides (ß = -0.144, p = 0.002), VLDL triglycerides (ß = -0.233, p < 0.001) and VLDL cholesterol (ß = -0.199, p < 0.001) and directly related to HDL cholesterol (ß = 0.126, p = 0.008). Watching TV and videos was directly related to the cardiometabolic risk score (ß = 0.135, p = 0.003), body fat percentage (ß = 0.090, p = 0.039), waist circumference (ß = 0.097, p = 0.033) and systolic blood pressure (ß = 0.096, p = 0.039). Resting was directly associated with the cardiometabolic risk score (ß = 0.092, p = 0.049), triglycerides (ß = 0.131, p = 0.005), VLDL triglycerides (ß = 0.134, p = 0.009), VLDL cholesterol (ß = 0.147, p = 0.004) and LDL cholesterol (ß = 0.105, p = 0.023). Other types of PA and SB had less consistent associations with cardiometabolic risk factors. CONCLUSIONS: The results of our study emphasise increasing total and unstructured PA and decreasing watching TV and videos and other sedentary behaviours to reduce cardiometabolic risk among children. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01803776.

Cross-sectional associations of food consumption with plasma fatty acid composition and estimated desaturase activities in Finnish children.

Plasma fatty acid (FA) composition is known to be an indicator of dietary fat quality, but the associations of other dietary factors with plasma FA composition remain unknown in children. We investigated the cross-sectional associations of food consumption with the proportions of FA and estimated desaturase activities in plasma cholesteryl esters (CE) and phospholipids (PL) among children. The subjects were a population sample of 423 children aged 6­8 years examined at baseline of The Physical Activity and Nutrition in Children (PANIC) Study. We assessed food consumption by food records and plasma FA composition by gas chromatography. We used linear regression models adjusted for age, sex, physical activity and total energy intake to analyze the associations. A higher consumption of vegetable oil-based margarine (fat 60­80 %) was associated with a higher proportion of linoleic and α-linolenic acids in plasma CE and PL. A higher consumption of high-fiber grain products was related to a lower proportion of oleic acid in CE and PL. The consumption of candy was directly associated with the proportion of palmitoleic and oleic acid in plasma CE. The consumption of vegetable oil-based margarine was inversely associated with estimated stearoyl-CoA-desaturase activity in plasma CE and PL and the consumption of candy was directly related to it in plasma CE. The results of our study suggest that plasma FA composition is not only a biomarker for dietary fat quality but also reflects the consumption of high-fiber grain products and foods high in sugar among children.

Association of erythrocyte membrane fatty acids with changes in glycemia and risk of type 2 diabetes.

BACKGROUND: The significance of erythrocyte membrane fatty acids (EMFAs) and their ratios to predict hyperglycemia and incident type 2 diabetes is unclear. OBJECTIVE: We investigated EMFAs as predictors of the worsening of hyperglycemia and incident type 2 diabetes in a 5-y follow-up of a population-based study. DESIGN: We measured EMFAs in 1346 Finnish men aged 45-73 y at baseline [mean ± SD age: 55 ± 6 y; body mass index (in kg/m(2)): 26.5 ± 3.5]. Our prospective follow-up study included only men who were nondiabetic at baseline and who had data available at the 5-y follow-up visit (n = 735). RESULTS: Our study showed that, after adjustment for confounding factors, palmitoleic acid (16:1n-7; P = 2.8 × 10(-7)), dihomo-γ-linolenic acid (20:3n-6; P = 2.3 × 10(-4)), the ratio of 16:1n-7 to 16:0 (P = 1.6 × 10(-8)) as a marker of stearoyl coenzyme A desaturase 1 activity, and the ratio of 20:3n-6 to 18:2n-6 (P = 9.4 × 10(-7)) as a marker of Δ(6)-desaturase activity significantly predicted the worsening of hyperglycemia (glucose area under the curve in an oral-glucose-tolerance test). In contrast, linoleic acid (18:2n-6; P = 0.0015) and the ratio of 18:1n-7 to 16:1n-7 (P = 1.5 × 10(-9)) as a marker of elongase activity had opposite associations. Statistical significance persisted even after adjustment for baseline insulin sensitivity, insulin secretion, and glycemia. Palmitoleic acid (P = 0.010) and the ratio of 16:1n-7 to 16:0 (P = 0.004) nominally predicted incident type 2 diabetes, whereas linoleic acid had an opposite association (P = 0.004), and n-3 polyunsaturated fatty acids did not show any associations. CONCLUSION: EMFAs and their ratios are associated longitudinally with changes in glycemia and the risk type 2 diabetes.

Dietary fat in relation to erythrocyte fatty acid composition in men.

Erythrocyte membrane fatty acid (EMFA) composition is used in the validation of food frequency questionnaires (FFQ) and the evaluation of dietary fat quality. In this cross-sectional study we aimed to investigate associations of diet with EMFA. Altogether, 1,033 randomly selected Finnish men, aged from 47 to 75 years filled in a FFQ and their EMFA composition was analyzed. Marine polyunsaturated fatty acid (PUFA) intake correlated positively with erythrocyte eicosapentaenoic and docosahexaenoic acids (r(s) = 0.415 and r(s) = 0.340, respectively, P < 0.001) and inversely with all n-6 PUFA analyzed (P < 0.001). PUFA intake from spreads and cooking fats correlated positively with alpha-linolenic (ALA), linoleic (LNA) and nervonic acids (r(s) = 0.229, r(s) = 0.160 and r(s) = 0.143, respectively, P < 0.001). Milk fat intake was associated with myristic and behenic acids (r(s) = 0.186 and r(s) = 0.132, respectively P < 0.001). Butter users had lower ALA and LNA proportions (mol%) than non-users (0.16 ± 0.04 vs. 0.19 ± 0.05, P < 0.001 and 7.77 ± 1.02 vs. 8.12 ± 1.11, P = 0.001). Higher PUFA intake from meat was related to decreased long-chain n-3 (P < 0.001) and increased n-6 PUFA (P < 0.001) proportions. In conclusion, EMFA composition reflects particularly well the intakes of n-3 PUFA, whereas other associations remained lower. Yet, all main sources of dietary fat were related with EMFA. The dietary effect on the nervonic acid proportion was confirmed.

Triacylglycerol fatty acid composition in diet-induced weight loss in subjects with abnormal glucose metabolism--the GENOBIN study.

BACKGROUND: The effect of weight loss on different plasma lipid subclasses at the molecular level is unknown. The aim of this study was to examine whether a diet-induced weight reduction result in changes in the extended plasma lipid profiles (lipidome) in subjects with features of metabolic syndrome in a 33-week intervention. METHODOLOGY/PRINCIPAL FINDINGS: Plasma samples of 9 subjects in the weight reduction group and 10 subjects in the control group were analyzed using mass spectrometry based lipidomic and fatty acid analyses. Body weight decreased in the weight reduction group by 7.8+/-2.9% (p<0.01). Most of the serum triacylglycerols and phosphatidylcholines were reduced. The decrease in triacylglycerols affected predominantly the saturated short chain fatty acids. This decrease of saturated short chain fatty acid containing triacylglycerols correlated with the increase of insulin sensitivity. However, levels of several longer chain fatty acids, including arachidonic and docosahexanoic acid, were not affected by weight loss. Levels of other lipids known to be associated with obesity such as sphingolipids and lysophosphatidylcholines were not altered by weight reduction. CONCLUSIONS/SIGNIFICANCE: Diet-induced weight loss caused significant changes in global lipid profiles in subjects with abnormal glucose metabolism. The observed changes may affect insulin sensitivity and glucose metabolism in these subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00621205.