Substitution analyses of foods with varying fat quality and the associations with all-cause mortality and impact of the FADS-1 genotype in elderly men.

PURPOSE: To investigate associations between substitutions of foods varying in fat quality and all-cause mortality in elderly Swedish men and to examine effect measure modification by a gene involved in fatty acid desaturation (rs174550 FADS1). METHODS: Using Cox-regression models in the ULSAM cohort (n = 1133 men aged 71), we aimed to investigate; (1) Associations between the substitution of a nutrient or food for another on all-cause mortality (primary outcome) and CVD (secondary outcome) and (2) Associations between the addition of various fat-rich foods to the habitual diet and all-cause mortality and CVD. Subgroup analyses based on the rs174550 FADS1 genotype were conducted. RESULTS: Over a mean follow-up of 11.6-13.7 years, n = 774 died and n = 494 developed CVD, respectively. No clear associations were observed for the vast majority of substitution nor addition models. Adding saturated fatty acids (SFA) on top of the habitual diet was however associated with an increased risk of mortality in men with the CT/CC-genotype [HR (95% CI) 1.44 (1.05, 1.97)]. Post-hoc analyses showed an inverse association of substituting SFA with carbohydrates [HR (95% CI) 0.79 (0.65, 0.97)], which was somewhat stronger in men with the CT/CC-genotype compared to men carrying the TT-genotype. CONCLUSIONS: Few associations were observed between diet and all-cause mortality and CVD in this population. However, substituting SFA with carbohydrates was associated with lower mortality in post-hoc analyses and adding SFA to the habitual diet increased mortality in men with the CT/CC-genotype. The latter observation is novel and warrants further investigation in larger cohort studies including women.

Contrasting Carbohydrate Quantity and Quality and the Effects on Plasma Saturated and Monounsaturated Fatty Acids in Healthy Adults: A Randomized Controlled Trial.

BACKGROUND: It is unclear whether moderate differences in dietary carbohydrate quantity and quality influence plasma FAs in the lipogenic pathway in healthy adults. OBJECTIVES: We investigated the effects of different carbohydrate quantities and quality on plasma palmitate concentrations (primary outcome) and other saturated and MUFAs in the lipogenic pathway. METHODS: Twenty healthy participants were randomly assigned, and 18 (50% women; age: 22-72 y; BMI: 18.2-32.7 kg/m2 and BMI was measured in kg/m2) started the cross-over intervention. During each 3-wk period (separated by a 1-wk washout period), 3 diets were consumed (all foods provided) in random order: low-carbohydrate (LC) (38% energy (E) carbohydrates, 25-35 g fiber/d, 0% E added sugars); high-carbohydrate/high-fiber (HCF) (53% E carbohydrates, 25-35 g fiber/d, 0% E added sugars); and high-carbohydrate/high-sugar (HCS) (53% E carbohydrates, 19-21 g fiber/d, 15% E added sugars). Individual FAs were measured proportionally to total FAs by GC in plasma cholesteryl esters, phospholipids, and TGs. False discovery rate-adjusted repeated measures ANOVA [ANOVA-false discovery rate (FDR)] was used to compare outcomes. RESULTS: The self-reported intakes of carbohydrates and added- and free sugars were; 30.6% E and 7.4% E in LC, 41.4% E and 6.9% E in HCF, and 45.7% E and 10.3% in HCS. Plasma palmitate did not differ between the diet periods (ANOVA FDR P > 0.43, n = 18). After HCS, myristate concentrations in cholesterol esters and phospholipids were ≥19% higher than LC and ≥22% higher than HCF (P = 0.005). After LC, palmitoleate in TG was 6% lower compared with HCF and 7% compared with HCS (P = 0.041). Body weight differed (≤0.75 kg) between diets before FDR correction. CONCLUSIONS: Different carbohydrate quantity and quality do not influence plasma palmitate concentrations after 3 wk in healthy Swedish adults, whereas myristate increased after the moderately higher intake of carbohydrate/high-sugar, but not carbohydrate/high-fiber. Whether plasma myristate is more responsive than palmitate to differences in carbohydrate intake requires further study, especially considering that participants deviated from the planned dietary targets. J Nutr 20XX;xx:xx-xx. This trial was registered at clinicaltrials.gov as NCT03295448.

Fatty Acid Proportions in Plasma Cholesterol Esters and Phospholipids Are Positively Correlated in Various Swedish Populations.

Background: Fatty acid (FA) proportions in cholesterol esters (CEs) and plasma phospholipids are widely used as dietary biomarkers. Information on how proportions in these fractions correlate could have implications for interpretation and use of FA biomarkers in observational and interventional studies.Objective: We investigated correlations between FA proportions in CEs and phospholipids in free-living individuals and assessed how diet-induced alterations of FA proportions correlate between fractions.Methods: Spearman's rank correlation coefficients (rs) between FA proportions (percentage of total FAs) in circulating CEs and phospholipids were calculated separately in 8 individual study populations including Swedish females and males (N = 2052; age range: 11-84 y), and pooled by inverse-variance weighted meta-analysis. In addition, study populations were stratified by age, sex, body mass index (BMI; in kg/m2), and diabetes status, and strata-specific rs were pooled by meta-analysis. In 2 randomized trials (N = 79) in which dietary saturated FAs were isocalorically replaced with unsaturated FAs, treatment-wise calculations of rs were conducted between FA changes in CEs and phospholipids.Results: Overall, FA proportions in CEs and phospholipids correlated well and especially strongly for polyunsaturated FAs (PUFAs), with pooled rs (95% CIs) ranging from 0.74 (0.72, 0.76) for α-linolenic acid to 0.92 (0.91, 0.93) for eicosapentaenoic acid. Weak correlations (pooled rs < 0.4) were observed only for palmitic acid and stearic acid, with pooled rs (95% CIs): 0.29 (0.24, 0.33) and 0.30 (0.25, 0.34), respectively. Overall, correlations were not affected by age, sex, BMI, or diabetes status. Strong correlations (rs ≥ 0.6) between diet-induced FA changes in CEs and phospholipids were observed for most PUFAs.Conclusions: Proportions of most FAs in CEs and phospholipids ranked individuals similarly, suggesting that FA proportions in these fractions can be used interchangeably in populations of diverse age, sex, body composition, and diabetes status. Caution is advised, however, when comparing results from studies assessing palmitic acid or stearic acid in different lipid fractions.

Fatty acid composition in serum cholesterol esters and phospholipids is linked to visceral and subcutaneous adipose tissue content in elderly individuals: a cross-sectional study.

BACKGROUND: Visceral adipose tissue (VAT) and truncal fat predict cardiometabolic disease. Intervention trials suggest that saturated fatty acids (SFA), e.g. palmitic acid, promote abdominal and liver fat storage whereas polyunsaturated fatty acids (PUFA), e.g. linoleic acid, prevent fat accumulation. Such findings require investigation in population-based studies of older individuals. We aimed to investigate the relationships of serum biomarkers of PUFA intake as well as serum levels of palmitic acid, with abdominal and total adipose tissue content. METHODS: In a population-based sample of 287 elderly subjects in the PIVUS cohort, we assessed fatty acid composition in serum cholesterol esters (CE) and phospholipids (PL) by gas chromatography and the amount of VAT and abdominal subcutaneous (SAT) adipose tissue by magnetic resonance imaging (MRI), liver fat by MR spectroscopy (MRS), and total body fat, trunk fat and leg fat by dual-energy X-ray absorptiometry (DXA). Insulin resistance was estimated by HOMA-IR. RESULTS: VAT and trunk fat showed the strongest correlation with insulin resistance (r = 0.49, P < 0.001). Linoleic acid in both CE and PL was inversely related to all body fat depots (r = -0.24 to -0.33, P < 0.001) including liver fat measured in a sub-group (r = -0.26, P < 0.05, n = 73), whereas n-3 PUFA showed weak inverse (18:3n-3) or positive (20:5n-3) associations. Palmitic acid in CE, but not in PL, was directly correlated with VAT (r = 0.19, P < 0.001) and trunk fat (r = 0.18, P = 0.003). Overall, the significant associations remained after adjusting for energy intake, height, alcohol, sex, smoking, education and physical activity. The inverse correlation between linoleic acid and VAT remained significant after further adjustment for total body fat. CONCLUSIONS: Serum linoleic acid is inversely related to body fat storage including VAT and trunk fat whereas palmitic acid was less consistently but directly associated, in line with recent feeding studies. Considering the close link between VAT and insulin resistance, a potential preventive role of plant-based PUFA in VAT accumulation warrants further study.

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding.

AIMS/HYPOTHESIS: Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. METHODS: mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. RESULTS: We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes- and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. CONCLUSIONS/INTERPRETATION: Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

A Healthy Nordic Diet Alters the Plasma Lipidomic Profile in Adults with Features of Metabolic Syndrome in a Multicenter Randomized Dietary Intervention.

BACKGROUND: A healthy Nordic diet is associated with improvements in cardiometabolic risk factors, but the effect on lipidomic profile is not known. OBJECTIVE: The aim was to investigate how a healthy Nordic diet affects the fasting plasma lipidomic profile in subjects with metabolic syndrome. METHODS: Men and women (n = 200) with features of metabolic syndrome [mean age: 55 y; body mass index (in kg/m2): 31.6] were randomly assigned to either a healthy Nordic (n = 104) or a control (n = 96) diet for 18 or 24 wk at 6 centers. Of the participants, 156 completed the study with plasma lipidomic measurements. The healthy Nordic diet consisted of whole grains, fruits, vegetables, berries, vegetable oils and margarines, fish, low-fat milk products, and low-fat meat. An average Nordic diet served as the control diet and included low-fiber cereal products, dairy fat-based spreads, regular-fat milk products, and a limited amount of fruits, vegetables, and berries. Lipidomic profiles were measured at baseline, week 12, and the end of the intervention (18 or 24 wk) by using ultraperformance liquid chromatography mass spectrometry. The effects of the diets on the lipid variables were analyzed with linear mixed-effects models. Data from centers with 18- or 24-wk duration were also analyzed separately. RESULTS: Changes in 21 plasma lipids differed significantly between the groups at week 12 (false discovery rate P < 0.05), including increases in plasmalogens and decreases in ceramides in the healthy Nordic diet group compared with the control group. At the end of the study, changes in lipidomic profiles did not differ between the groups. However, when the intervention lasted 24 wk, changes in 8 plasma lipids that had been identified at 12 wk, including plasmalogens, were sustained. There were no differences in changes in plasma lipids between groups with an intervention of 18 wk. By the dietary biomarker score, adherence to diet did not explain the difference in the results related to the duration of the study. CONCLUSIONS: A healthy Nordic diet transiently modified the plasma lipidomic profile, specifically by increasing the concentrations of antioxidative plasmalogens and decreasing insulin resistance-inducing ceramides. This trial was registered at clinicaltrials.gov as NCT00992641.

Saturated fatty acids in human visceral adipose tissue are associated with increased 11- ß-hydroxysteroid-dehydrogenase type 1 expression.

BACKGROUND: Visceral fat accumulation is associated with metabolic disease. It is therefore relevant to study factors that regulate adipose tissue distribution. Recent data shows that overeating saturated fatty acids promotes greater visceral fat storage than overeating unsaturated fatty acids. Visceral adiposity is observed in states of hypercortisolism, and the enzyme 11-ß-hydroxysteroid-dehydrogenase type 1 (11ß-hsd1) is a major regulator of cortisol activity by converting inactive cortisone to cortisol in adipose tissue. We hypothesized that tissue fatty acid composition regulates body fat distribution through local effects on the expression of 11ß-hsd1 and its corresponding gene (HSD11B1) resulting in altered cortisol activity. FINDINGS: Visceral- and subcutaneous adipose tissue biopsies were collected during Roux-en-Y gastric bypass surgery from 45 obese women (BMI; 41±4 kg/m2). The fatty acid composition of each biopsy was measured and correlated to the mRNA levels of HSD11B1. 11ß-hsd1 protein levels were determined in a subgroup (n=12) by western blot analysis. Our main finding was that tissue saturated fatty acids (e.g. palmitate) were associated with increased 11ß-hsd1 gene- and protein-expression in visceral but not subcutaneous adipose tissue. CONCLUSIONS: The present study proposes a link between HSD11B1 and saturated fatty acids in visceral, but not subcutaneous adipose tissue. Nutritional regulation of visceral fat mass through HSD11B1 is of interest for the modulation of metabolic risk and warrants further investigation.

A dietary biomarker approach captures compliance and cardiometabolic effects of a healthy Nordic diet in individuals with metabolic syndrome.

Assessment of compliance with dietary interventions is necessary to understand the observed magnitude of the health effects of the diet per se. To avoid reporting bias, different dietary biomarkers (DBs) could be used instead of self-reported data. However, few studies investigated a combination of DBs to assess compliance and its influence on cardiometabolic risk factors. The objectives of this study were to use a combination of DBs to assess compliance and to investigate how a healthy Nordic diet (ND) influences cardiometabolic risk factors in participants with high apparent compliance compared with the whole study population. From a recently conducted isocaloric randomized trial, SYSDIET (Systems Biology in Controlled Dietary Interventions and Cohort Studies), in 166 individuals with metabolic syndrome, several DBs were assessed to reflect different key components of the ND: canola oil (serum phospholipid α-linolenic acid), fatty fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], vegetables (plasma ß-carotene), and whole grains (plasma alkylresorcinols). High-fat dairy intake (expectedly low in the ND) was reflected by serum pentadecanoic acid. All participants with biomarker data (n = 154) were included in the analyses. Biomarkers were combined by using a biomarker rank score (DB score) and principal component analysis (PCA). The DB score was then used to assess compliance. During the intervention, median concentrations of alkylresorcinols, α-linolenic acid, EPA, and DHA were >25% higher in the ND individuals than in the controls (P < 0.05), whereas median concentrations of pentadecanoic acid were 14% higher in controls (P < 0.05). Median DB score was 57% higher in the ND than in controls (P < 0.001) during the intervention, and participants were ranked similarly by DB score and PCA score. Overall, estimates of group difference in cardiometabolic effects generally appeared to be greater among compliant participants than in the whole study population (e.g., estimates of treatment effects on blood pressure and lipoproteins were ∼1.5- to 2-fold greater in the most compliant participants), suggesting that poor compliance attenuated the dietary effects. With adequate consideration of their limitations, DB combinations (e.g., DB score) could be useful for assessing compliance in intervention studies investigating cardiometabolic effects of healthy dietary patterns. The study was registered at clinicaltrials.gov as NCT00992641.

Effects of a healthy Nordic diet on plasma 25-hydroxyvitamin D concentration in subjects with metabolic syndrome: a randomized, [corrected] controlled trial (SYSDIET).

PURPOSE: At northern latitudes, vitamin D is not synthesized endogenously during winter, causing low plasma 25-hydroxyvitamin D (25(OH)D) concentrations. Therefore, we evaluated the effects of a healthy Nordic diet based on Nordic nutrition recommendations (NNR) on plasma 25(OH)D and explored its dietary predictors. METHODS: In a Nordic multi-centre trial, subjects (n = 213) with metabolic syndrome were randomized to a control or a healthy Nordic diet favouring fish (≥300 g/week, including ≥200 g/week fatty fish), whole-grain products, berries, fruits, vegetables, rapeseed oil and low-fat dairy products. Plasma 25(OH)D and parathyroid hormone were analysed before and after 18- to 24-week intervention. RESULTS: At baseline, 45 % had vitamin D inadequacy (<50 nmol/l), whereas 8 % had deficiency (<25 nmol/l). Dietary vitamin D intake was increased by the healthy Nordic diet (P < 0.001). The healthy Nordic and the control diet reduced the prevalence of vitamin D inadequacy by 42 % (P < 0.001) and 19 % (P = 0.002), respectively, without between-group difference (P = 0.142). Compared with control, plasma 25(OH)D (P = 0.208) and parathyroid hormone (P = 0.207) were not altered by the healthy Nordic diet. Predictors for 25(OH)D were intake of vitamin D, eicosapentaenoic acids (EPA), docosahexaenoic acids (DHA), vitamin D supplement, plasma EPA and plasma DHA. Nevertheless, only vitamin D intake and season predicted the 25(OH)D changes. CONCLUSION: Consuming a healthy Nordic diet based on NNR increased vitamin D intake but not plasma 25(OH)D concentration. The reason why fish consumption did not improve vitamin D status might be that many fish are farmed and might contain little vitamin D or that frying fish may result in vitamin D extraction. Additional ways to improve vitamin D status in Nordic countries may be needed.

Fats and oils - a scoping review for Nordic Nutrition Recommendations 2023.

This scoping review for the Nordic Nutrition Recommendations 2023 summarizes the available evidence on fats and oils from a food level perspective. A literature search for systematic reviews (SRs) and meta-analyses was conducted in PubMed. There are few SRs and meta-analyses available that investigate the association between fats and oils (food level) and health outcomes; the majority report associations at the nutrient level (fatty acid classes). All identified SRs and meta-analyses were of low methodological quality, thus the findings and conclusions presented within this scoping review should be interpreted cautiously. Based on this limited evidence, the following results were indicated: the intake of olive oil may be associated with reduced risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and total mortality in prospective cohort studies. The intake of butter was not associated with the risk of CVD but may be related to slightly lower risk of T2D and higher risk of total mortality in prospective cohort studies. For cancer, the evidence is sparse and primarily based on case-control studies. The intake of olive oil may be associated with reduced risk of cancer, whereas the intake of butter may be associated with increased risk of certain cancer types. Butter increases LDL-cholesterol when compared to virtually all other fats and oils. Palm oil may increase LDL-cholesterol when compared to oils rich in MUFA or PUFA but may not have any effect on glucose or insulin. Coconut oil may increase LDL-cholesterol when compared to other plant oils but may decrease LDL-cholesterol when compared to animal fats rich in SFA. Canola/rapeseed oil may decrease LDL-cholesterol compared to olive oil, sunflower oil and sources of SFA and may also reduce body weight compared to other oils. Olive oil may decrease some inflammation markers but may not have a differential effect on LDL-cholesterol compared to other fats and oils. The effect on risk markers likely differs depending on the type/version of oil, for example, due to the presence of polyphenols, phytosterols and other minor components. Taken together, based on the available evidence, oils rich in unsaturated fat (e.g. olive oil, canola oil) are to be preferred over oils and fats rich in saturated fat (e.g. butter, tropical oils).

Fat and fatty acids - a scoping review for Nordic Nutrition Recommendations 2023.

Two de novo NNR2022 systematic reviews (SRs) as well as 21 qualified SRs (qSRs) were available. A literature search yielded an additional ~70 SRs, meta-analyses and biomarker papers. Diets lower in total fat are associated with reductions in body weight and blood pressure compared with diets higher in total fat in adults. Partial replacement of saturated fatty acid (SFA) with n-6 polyunsaturated fatty acid (PUFA) improves blood lipid profile, decreases the risk of cardiovascular disease (CVD), improves glucose-insulin homeostasis and may decrease the risk of total mortality. Long-chain n-3 PUFAs (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) decrease triglycerides and are associated with lower risk of CVD. Dietary PUFAs, both n-3 and n-6, may be associated with reduced risk of type 2 diabetes (T2D). There is inconclusive evidence to suggest that the type of dietary fat is associated with blood pressure, risk of hypertension or musculoskeletal health. Higher intake of total PUFA is associated with lower mortality from any cancer. Long-chain n-3 PUFA is associated with reduced risk of breast cancer, whereas biomarker levels of n-6 PUFA are associated with lower risk of any cancer. Intake of long-chain n-3 PUFA during pregnancy increases length of gestation and child birth weight and reduces the risk of preterm delivery, but there is inconclusive evidence to suggest that it may influence child neurodevelopment, growth or development of allergic disease. In studies with higher versus lower dietary cholesterol intake levels, total blood cholesterol increased or were unaffected by the dietary cholesterol, resulting in inconclusive results. Trans fatty acid (TFA), regardless of source, impairs blood lipid profile compared to unsaturated fat. In observational studies, TFA is positively associated with CVD and total mortality but whether associations differ by source is inconclusive. Ruminant TFA, as well as biomarker levels of odd-chain fatty acids, might be associated with lower risk of T2D.

Glycemic variability assessed using continuous glucose monitoring in individuals without diabetes and associations with cardiometabolic risk markers: A systematic review and meta-analysis.

BACKGROUND & AIMS: Continuous glucose monitoring (CGM) provides data on short-term glycemic variability (GV). GV is associated with adverse outcomes in individuals with diabetes. Whether GV is associated with cardiometabolic risk in individuals without diabetes is unclear. We systematically reviewed the literature to assess whether GV is associated with cardiometabolic risk markers or outcomes in individuals without diabetes. METHODS: Searches were performed in PubMed/Medline, Embase and Cochrane from inception through April 2022. Two researchers were involved in study selection, data extraction and quality assessment. Studies evaluating GV using CGM for ≥24 h were included. Studies in populations with acute and/or critical illness were excluded. Both narrative synthesis and meta-analyzes were performed, depending on outcome. RESULTS: Seventy-one studies were included; the majority were cross-sectional. Multiple measures of GV are higher in individuals with compared to without prediabetes and GV appears to be inversely associated with beta cell function. In contrast, GV is not clearly associated with insulin sensitivity, fatty liver disease, adiposity, blood lipids, blood pressure or oxidative stress. However, GV may be positively associated with the degree of atherosclerosis and cardiovascular events in individuals with coronary disease. CONCLUSION: GV is elevated in prediabetes, potentially related to beta cell dysfunction, but less clearly associated with obesity or traditional risk factors. GV is associated with coronary atherosclerosis development and may predict cardiovascular events and type 2 diabetes. Prospective studies are warranted, investigating the predictive power of GV in relation to incident disease. GV may be an important risk measure also in individuals without diabetes.

Substitutions of saturated fat intakes with other macronutrients and foods and risk of NAFLD cirrhosis and all-cause hepatocellular carcinoma: a prospective cohort study.

BACKGROUND: Short-term trials have shown a reduction in liver fat when saturated fatty acids (SFAs) are substituted with polyunsaturated fatty acids (PUFA), or with low-glycemic carbohydrates. However, few cohort studies have been conducted to investigate the associations of replacing SFA and SFA-rich foods with different macronutrients and foods in more severe stages of liver disease; nonalcoholic fatty liver disease (NAFLD) cirrhosis and hepatocellular carcinoma (HCC). OBJECTIVES: To investigate associations between the substitution of SFA and SFA-rich foods with other macronutrients and foods and NAFLD cirrhosis and HCC in a middle-aged to elderly Swedish population of n = 77,059 males and females. METHODS: Time-to-event analyses were performed to investigate associations between the food and macronutrient substitutions and NAFLD cirrhosis and HCC. Multivariable Cox regression models were constructed to estimate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Statistical isocaloric and equal-mass substitutions were performed using the leave-one-out method. Prespecified nutrient and food substitutions of interest were SFA with carbohydrates, SFA with fiber, SFA with PUFA, butter with margarine and vegetable oils, unprocessed red meat with fish, and milk with fermented milk. RESULTS: Over a median follow-up of 24 y, 566 cases of NAFLD cirrhosis and 205 cases of HCC were registered. Overall, dietary substitutions showed no clear associations with either NAFLD cirrhosis or HCC. Substituting SFA with carbohydrates showed an HR of 0.87 (95% CI: 0.74, 1.02) for HCC and 1.00 (95% CI: 0.89, 1.11) for NAFLD cirrhosis. Substituting milk with fermented milk showed an HR of 0.93 (95% CI: 0.85, 1.01) for HCC and 0.97 (95% CI: 0.92, 1.03) for NAFLD cirrhosis. CONCLUSIONS: No clear associations were observed between diet and NAFLD cirrhosis or HCC. Although accompanied by low precision, possible lowered risks of HCC by substituting SFA with carbohydrates or milk with fermented milk might be of interest, but needs replication in other cohorts.

Overfeeding polyunsaturated fat compared with saturated fat does not differentially influence lean tissue accumulation in individuals with overweight: a randomized controlled trial.

BACKGROUND: Fatty acids may influence lean tissue volume and skeletal muscle function. We previously reported in young lean participants that overfeeding PUFA compared with SFA induced greater lean tissue accumulation despite similar weight gain. OBJECTIVES: In a double-blind randomized controlled trial, we aimed to investigate if the differential effects of overfeeding SFA and PUFA on lean tissue accumulation could be replicated in individuals with overweight and identify potential determinants. Further, using substitution models, we investigated associations between SFA and PUFA concentrations with lean tissue volume in a large population-based sample (UK Biobank). METHODS: Sixty-one males and females with overweight [BMI (kg/m2): 27.3 (interquartile range (IQR), 25.4-29.3); age: 43 (IQR, 36-48)] were overfed SFA (palm oil) or n-6 (ω-6) PUFA (sunflower oil) for 8 wk. Lean tissue was assessed by MRI. We had access to n = 13,849 participants with data on diet, covariates, and MRI measurements of lean tissue, as well as 9119 participants with data on circulating fatty acids in the UK Biobank. RESULTS: Body weight gain mean (SD) was similar in PUFA (2.01 ± 1.90 kg) and SFA (2.31 ± 1.38 kg) groups. Lean tissue increased to a similar extent [0.54 ± 0.93 L and 0.67 ± 1.21 L for PUFA and SFA groups, respectively, with a difference between groups of 0.07 (-0.21, 0.35)]. We observed no differential effects on circulating amino acids, myostatin, or IL-15 and no clear determinants of lean tissue accumulation. Similar nonsignificant results for SFA and PUFA were observed in UK Biobank, but circulating fatty acids demonstrated ambiguous and sex-dependent associations. CONCLUSIONS: Overfeeding SFA or PUFA does not differentially affect lean tissue accumulation during 8 wk in individuals with overweight. A lack of dietary fat type-specific effects on lean tissue is supported by specified substitution models in a large population-based cohort consuming their habitual diet. This trial was registered at clinicaltrials.gov identifier as NCT02211612.

Plasma alkylresorcinols reflect important whole-grain components of a healthy Nordic diet.

Biomarkers of dietary intake can be important tools in nutrition research. Our aim was to assess whether plasma alkylresorcinol (AR) and ß-carotene concentrations could be used as dietary biomarkers for whole-grain, fruits and vegetables in a healthy Nordic diet (ND). Participants (n = 166), 30-65 y with a body mass index of 27-40 kg/m(2) and two more features of metabolic syndrome (International Diabetes Federation definition, slightly modified), were recruited through six centers in the Nordic countries and randomly assigned to an ND or control diet for 18 or 24 wk, depending on study center. Plasma AR and ß-carotene were analyzed and nutrient intake calculated from 4-d food records. Median fiber intake increased in the ND group from 2.5 g/MJ at baseline to 4.1 g/MJ (P < 0.001) at end point (week 18 or 24), and median (IQR) fasting plasma total AR concentration increased from 73 (88) to 106 (108) nmol/L, or 45%, from baseline to end point (P < 0.001). The AR concentration was significantly higher in the ND group (P < 0.001) than in the control group at end point. ß-Carotene intake tended to increase in the ND group (P = 0.07), but the plasma ß-carotene concentration did not change significantly throughout the study and did not differ between the groups at follow-up. In conclusion, an ND resulted in higher dietary fiber intake and increased plasma total AR concentration compared with the control diet, showing that the total AR concentration might be a valid biomarker for an ND in which whole-grain wheat and rye are important components. No significant difference in plasma ß-carotene concentrations was observed between the ND and control groups, suggesting that ß-carotene may not be a sensitive enough biomarker of the ND.

Diet composition, nutrient substitutions and circulating fatty acids in relation to ectopic and visceral fat depots.

BACKGROUND & AIMS: Short-term randomized trials have demonstrated that replacing saturated fat (SFA) with polyunsaturated fat (PUFA) causes a reduction or prevention of liver fat accumulation, but population-based studies on diet and body fat distribution are limited. We investigated cross-sectional associations between diet, circulating fatty acids and liver fat, visceral adipose tissue (VAT), intermuscular adipose tissue (IMAT) and other fat depots using different energy-adjustment models. METHODS: Sex-stratified analyses of n = 9119 (for serum fatty acids) to 13 849 (for nutrients) participants in UK Biobank were conducted. Fat depots were assessed by MRI, circulating fatty acids by NMR spectroscopy and diet by repeated 24-h recalls. Liver fat, VAT and IMAT were primary outcomes; total adipose tissue (TAT) and abdominal subcutaneous adipose tissue (ASAT) were secondary outcomes. Three a priori defined models were constructed: the all-components model, standard model and leave-one-out model (main model including specified nutrient substitutions). Imiomics (MRI-derived) was used to confirm and visualize associations. RESULTS: In women, substituting carbohydrates and free sugars with saturated fat (SFA) was positively associated with liver fat (ß (95% CI) = 0.19 (0.02, 0.36) and ß (95% CI) = 0.20 (0.05-0.35), respectively) and IMAT (ß (95% CI) = 0.07 (0.00, 0.14) and ß (95% CI) = 0.08 (0.02, 0.13), respectively), whereas substituting animal fat with plant fat was inversely associated with IMAT, ASAT and TAT. In the all-components and standard models, SFA and animal fat were positively associated with liver fat, IMAT and VAT whereas plant fat was inversely associated with IMAT in women. Few associations were observed in men. Circulating polyunsaturated fatty acids (PUFA) were inversely associated with liver fat, IMAT and VAT in both men and women, whereas SFA and monounsaturated fatty acids were positively associated. CONCLUSIONS: Type of dietary fat may be an important determinant of ectopic fat in humans consuming their habitual diet. Plant fat and PUFA should be preferred over animal fat and SFA. This is corroborated by circulating fatty acids and overall consistent through different energy adjustment models. TWITTER SUMMARY: In UK Biobank, intake of saturated- and animal fat were positively whereas biomarkers of polyunsaturated fat were inversely associated with liver-, visceral- and intermuscular fat. Type of dietary fat may be a determinant of ectopic fat, a risk factor for cardiometabolic disease.

The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.

The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma ß-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma ß-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.

Intake of Ultra-Processed Food and Ectopic-, Visceral- and Other Fat Depots: A Cross-Sectional Study.

Introduction: The purpose of this study was to investigate associations between intake of ultra-processed food (UPF) and liver fat, pancreas fat and visceral adipose tissue (VAT) but also subcutaneous adipose tissue (SAT), VAT/SAT ratio and total fat mass. Materials and Methods: Cross-sectional analysis of n = 286 50-year old men and women. Energy percentage (%E) from UPF was calculated from a semi-quantitative food frequency questionnaire. Food items were categorized according to the NOVA-classification system and fat depots were assessed using magnetic resonance imaging (MRI) and bioelectrical impedance analysis (BIA). Associations were analyzed using linear regression, adjusted for sex, education, physical activity, smoking, dietary factors and BMI. Results: Mean intake of UPF was 37.8 ± 10.2 %E and the three largest contributors to this were crisp- and wholegrain breads and spreads, indicating overall healthy food choices. Consumption of UPF was associated with higher intake of energy, carbohydrates and fiber and lower intake of protein and polyunsaturated fat but no differences were observed for total fat, saturated fat (SFA), monounsaturated fat, sugar or alcohol between tertiles of UPF. Intake of UPF was positively associated with liver- and pancreas fat, VAT, VAT/SAT and inversely associated with total fat mass in crude models. The association for VAT remained after full adjustment (ß = 0.01 (95% CI: 0.002, 0.02), P = 0.02) and was driven by women. Conclusion: Energy intake from UPF is not associated with ectopic fat, SAT or total fat after adjustment for multiple confounders in this population having overall healthy food habits. However, a positive association between UPF and VAT was observed which was driven by women.

Circulating fatty acids from high-throughput metabolomics platforms as potential biomarkers of dietary fatty acids.

BACKGROUND: Some fatty acids, i.e. n-3 and n-6 polyunsaturated fatty acids (PUFA), from metabolomics platforms based on nuclear magnetic resonance imaging (NMR) or liquid chromatography mass-spectrometry (LC-MS) are suggested to reflect dietary exposure. NMR and LC-MS are both relatively fast and cheap, however few studies have investigated their validity. Linoleic acid (LA) and docosahexaenoic acid (DHA), measured using gas chromatography (GC), are established biomarkers of dietary n-6 and n-3 PUFA intake, respectively. OBJECTIVE: To examine if circulating fatty acids derived from two commonly applied metabolomics platforms (using NMR and LC-MS) provide similar information compared to GC in two pooled population-based cohorts, one patient cohort, and in a randomized controlled trial (RCT). METHODS: Spearman rank correlations were conducted between LA and DHA in cholesteryl esters (CE) from GC and whole serum/plasma LA and DHA from the metabolomics platforms in a pooled population-based cohort of men and women (n Ëœ 1100) (primary analysis). Secondary correlation analyses included fatty acid classes such as n-3 PUFA, n-6 PUFA, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and total PUFA. Additionally, correlations were investigated for LA, DHA and the five fatty acid classes in phospholipids (PL), triacylglycerols (TAG) and non-esterified fatty acids (NEFA) in a RCT of n = 60 as well as in a population with biopsy-verified non-alcoholic fatty liver disease (NAFLD) (n = 59). Misclassification was examined using cross-tabulation and visualized using alluvial plots. RESULTS: Moderate to strong correlations (r = 0.51-0.81) were observed for LA and DHA in multiple lipid fractions in all cohorts using the NMR platform. For the pooled cohort, LA (r = 0.67, P < 0.0001) and DHA (r = 0.68, P < 0.0001) assessed in CE were strongly correlated with LA and DHA derived using NMR. Nearly half (49%) were correctly classified into their respective quartiles. Using LC-MS, only DHA (r = 0.44, P < 0.0001) demonstrated moderate correlations with DHA from GC. CONCLUSIONS: Unless fatty acid data from GC analysis is available or feasible, NMR-based technology might be a better option than a LC-MS-based platform, at least for certain PUFA. This should be taken into account in future studies aiming to use circulating fatty acids as dietary biomarkers for the investigation of diet-disease relationships.

Effects of sugar-sweetened soda on plasma saturated and monounsaturated fatty acids in individuals with obesity: A randomized study.

Background: High carbohydrate, i.e., sugars, intake potentially drives the liver into a lipogenic state leading to elevated plasma fatty acids. Excessive intake of saturated fat and sugar-sweetened soda induces liver fat accumulation, but studying the effect of high intake from sugar-sweetened soda on the de novo lipogenesis (DNL) fatty acids in long-term randomized trials is lacking. Objective: To study the effect of consuming 1 L/day of sugar-sweetened soda, semi-skimmed milk (milk), aspartame-sweetened soda or water over 24 weeks on DNL-derived fatty acids (i.e., palmitate (primary outcome) and other saturated and monounsaturated fatty acids), and markers of stearoyl-CoA desaturase activity (SCD1) in plasma phospholipids (PL), cholesteryl esters (CE), and triglycerides (TG). Design and methods: A randomized parallel study was conducted simultaneously at Aarhus University Hospital and Copenhagen University, Denmark, including (n = 41) individuals aged 20-50 years, with BMI of 26-40 kg/m2, and without diabetes. The groups consisted of 9 individuals in the sugar-sweetened soda, 10 in the milk, 11 in the aspartame-sweetened soda, and 11 in the water. The change at 24 weeks was assessed and compared across the groups using ANCOVA and mixed-effects models. Correlations of fatty acid changes with liver fat accumulation (magnetic resonance imaging) were explored. Results: After 24 weeks, the groups differed in palmitate proportions in PL, oleate in CE and PL, and palmitoleate and SCD1 in all fractions (p < 0.05). Compared with water, the relative proportion of palmitate in PL increased by approximately 1% during both sugar-sweetened soda (p = 0.011) and milk (p = 0.006), whereas oleate and palmitoleate increased only during sugar-sweetened soda (CE 2.77%, p < 0.001; PL 1.51%, p = 0.002 and CE 1.46%, PL 0.24%, TG 1.31%, all p < 0.001, respectively). Liver fat accumulation correlated consistently with changes in palmitoleate, whereas correlations with palmitate and oleate were inconsistent across lipid fractions. Conclusions: Although both sugar-sweetened soda and milk increased palmitate in PL, only excess intake of sugar-sweetened soda increased palmitoleate in all lipid fractions and correlated with liver fat. In contrast, isocaloric milk intake did not increase plasma monounsaturated fatty acids. Clinical trial registration: [https://clinicaltrials.gov/ct2/show/NCT00777647], identifier [NCT00777647].