Plasma Docosahexaenoic Acid Research Articles

APOE4 mice rely more on the plasma DHA than APOE3 mice, especially in glia morphology and cognitive performance.

AbstractBackgroundThe metabolism of docosahexaenoic acid (DHA), an omega‐3 fatty acid, is different in APOE4 carriers. Brain relies on the plasma DHA pool for its need but the plasma‐liver‐brain axis in relation to cognition remains obscure. We hypothesized that this relation is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice.MethodMale and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. Barnes maze and object recognition tests were performed in mice. Immunofluorescence was eprformed on parafin embeded brain slides with GFAP and IBA‐1 and multiplex cytokines were measured in hippocampus protein extracts.ResultIn the cortex, a genotype effect was found where APOE4 mice had higher concentration of DHA than APOE3 mice fed the control diet. APOE4 mice had 20‐30% lower plasma DHA and arachidonic acid (AA) concentrations, adipose tissue AA concentrations than APOE3 mice, independent of diet. In APOE4 mice, there was a significant correlation between plasma DHA and scores on the Barnes maze and with better recognition index. In addition, APOE4 mice fed the DHA diet had lower hippocampal concentrations of interleukin‐7, lipopolysaccharide‐induced CXC chemokine and monocyte chemoattractant protein 1, and higher concentration of interferon‐gamma compared to APOE4 mice fed the control diet. We also found that a diet rich in DHA enhances reactive astrogliosis and ramified microglia morphology in APOE4 mice.ConclusionAltogether, our data support that APOE4 mice rely more on the plasma DHA than APOE3 mice, especially in cognitive performance and astrocytes and microglia morphology. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Specialized Pro-Resolving Mediator (SPM) Profile in Blood from Children with Sickle Cell Disease (SCD): Comparison with Age-, and Race- Matched Controls

Introduction: Specialized Pro-resolving Mediators (SPMs) are lipid mediators, biosynthesized from the n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA); and the n-6 PUFA arachidonic acid (AA). SPMs are grouped into four families of lipid mediators including resolvins, protectins, maresins and lipoxins; and these mediators play a role in the resolution of inflammation. Inflammation plays a crucial role in the pathogenesis of clinical complications in sickle cell disease (SCD). In addition, multiple studies in SCD have documented decreased levels of anti-inflammatory fatty acids DHA and EPA in blood cells and plasma. We assessed whether the decreased DHA and EPA content play a role in modulation of peripheral blood SPM levels in SCD. Methods: Using targeted liquid chromatography (LC)-tandem mass spectrometry (MS/MS), we investigated plasma SPM profile in children with SCD in steady state (n=45, subjects with confirmed SCD genotypes SS and Sβ0 thalassemia, ages 2-20 years), and compared to that from an age- and race-matched control group (n=24). Analysis also included the SPM pathway markers, prostaglandins, thromboxane and leukotriene and their metabolites. (n-3) PUFA content in total blood cells was measured in both groups using capillary gas chromatography. Results: Consistent with the published results, a significant decrease in (n-3) PUFA content (measured as percent of total fatty acids) was noted in children with SCD (2.14% ± 0.47% in SCD vs 2.39% ± 0.45% in control, mean ± SD, P=0.04). In plasma from both SCD and controls, we identified and quantitated 6 SPMs which included DHA-derived resolvin (Rv) D1, RvD3 and 17R-RvD3; EPA-derived RvE2; and DPA(n-3)-derived RvD5(n-3) and protectin D (PD)-1 (n-3). Median RvD1 level (pg/ml) in SCD plasma was significantly elevated (65 in SCD vs 36 in controls, P=0.002). Levels of other SPMs were not significantly different between the two groups. Multiple SPM pathway markers including mono-hydroxy-PUFAs (EPA-derived 5-HEPE, 12-HEPE, 15-HEPE and 18-HEPE; DHA-derived 4-HDHA, 7-HDHA and 14-HDHA; and AA-derived 5-HETE, 12-HETE and 15-HETE) were present in both control and SCD plasma. Levels (median, pg/ml) of 5-lipoxygenase-derived EPA-metabolite 5-HEPE (212 vs 122, P=0.027) and DHA-derived metabolite 7-HDHA (62 vs 39, P=0.036), and 12-lipoxygenase-derived AA-metabolite 12-HETE (16783 vs 11796, P=0.025) were increased significantly in SCD compared to those from the controls. 15-Lipoxygenase derived pathway markers (15-HEPE and 15-HETE) were not different between the two groups. The cyclo-oxygenase-derived eicosanoids identified and quantitated in both groups included PGE2, PGD2 and TxB2 with a significant increase observed in TxB2 level in SCD plasma (1213 vs 970 pg/ml, P=0.038). Leukotriene (LT) B4 (an AA-derived pro-inflammatory mediator) and lipoxins (AA-derived SPMs), and their metabolites 20-OH-LTB4 and 20-COOH-LTB4 were absent in plasma from both SCD and control. Conclusions: Our results taken together demonstrate that the decreased bioavailability of (n-3) PUFA in children with SCD does not appear to limit SPM production in steady state as documented with normal/increased plasma levels of SPMs and their pathway markers. Whether the SPM profile in circulation is different in SCD pathologies associated with inflammation including vaso-occlusive pain crisis and acute chest syndrome, compared to steady state disease, require further investigation.

The fish paradox: people with low socio-economic status are not consuming the right type of fish

Abstract Background Fish intake is included in several national food-based dietary guidelines as a component of healthy diet because of its rich source of beneficial omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, heterogeneity among types of fish intake is rarely studied. We investigated the associations of socio-economic status (SES) with total and types of fish intake and validated whether types of fish intake was associated with plasma EPA and DHA. Methods From the Lifelines cohort study, 94 246 participants aged 44 ± 13 years old were included to test the association of two SES indicators, i.e., education level and income level, with dietary intakes of total, fatty, lean, fried, and other types of fish. Plasma EPA and DHA were measured in a minor subset of 575 participants (mean age: 50 ± 13 years old). Total and types of fish intake was assessed using Food Frequency Questionnaire. Linear regressions were applied, adjusted for relevant covariates. Results After adjusting for covariates, middle and low education were negatively associated with total, fatty, lean, and other fish intake (p < 0.001 for all), and positively associated with fried fish intake (β (SE): 0.04 (0.04), p < 0.001 for middle education; 0.07 (0.04), p < 0.001 for high education), with high education as the reference group. Similar results were observed for income level. In the subset population, total and fatty fish were positively associated with plasma EPA and DHA (p < 0.02 for all). Lean and other fish intake were positively associated with only DHA (p < 0.008 for all), but not EPA, while fried fish was not associated with either EPA or DHA in plasma (p > 0.1 for all). Conclusions Lower SES was associated with higher intake of fried fish, which did not seem to be associated with the fish-based EPA and DHA in plasma. Both nutrition education and food price policy could be implemented to increase the awareness and shape people's choice on types of fish. Key messages • People with low socio-economic status are consuming the type of fish that is not associated with fish-based omega-3 fatty acids, so nutrition education focusing on avoidance of fried fish is needed. • Food subsidy programs promoting intake and increasing affordability of healthier fish are needed to improve the nutritional awareness and status of our population.

Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele

The metabolism of docosahexaenoic acid (DHA), an omega-3 fatty acid, is different in carriers of APOE4, the main genetic risk factor for late-onset Alzheimer's disease. The brain relies on the plasma DHA pool for its need, but the plasma-liver-brain axis in relation to cognition remains obscure. We hypothesized that this relationship is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice. Male and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. There was a significant genotype × diet interaction for DHA concentration in the liver and adipose tissue. In the cortex, a genotype effect was found where APOE4 mice had a higher concentration of DHA than APOE3 mice fed the control diet. There was a significant genotype × diet interaction for the liver and hippocampal arachidonic acid (AA). APOE4 mice had 20–30% lower plasma DHA and AA concentrations than APOE3 mice, independent of diet. Plasma and liver DHA levels were significantly correlated in APOE3 and APOE4 mice. In APOE4 mice, there was a significant correlation between plasma, adipose tissues, cortex DHA and the Barnes maze and/or with a better recognition index. Moreover, higher AA levels in the liver and the hippocampus of APOE4 mice were correlated with lower cognitive performance. Our results suggest that there is a plasma-liver-brain axis of DHA that is modified in APOE4 mice. Moreover, our data support that APOE4 mice rely more on plasma DHA than APOE3 mice, especially in cognitive performance. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Altered Cord Blood Lipid Concentrations Correlate with Birth Weight and Doppler Velocimetry of Fetal Vessels in Human Fetal Growth Restriction Pregnancies.

Fetal growth restriction (FGR) is associated with short- and long-term morbidity, often with fetal compromise in utero, evidenced by abnormal Doppler velocimetry of fetal vessels. Lipids are vital for growth and development, but metabolism in FGR pregnancy, where fetuses do not grow to full genetic potential, is poorly understood. We hypothesize that triglyceride concentrations are increased in placentas and that important complex lipids are reduced in cord plasma from pregnancies producing the smallest babies (birth weight < 5%) and correlate with ultrasound Dopplers. Dopplers (umbilical artery, UA; middle cerebral artery, MCA) were assessed longitudinally in pregnancies diagnosed with estimated fetal weight (EFW) < 10% at ≥29 weeks gestation. For a subset of enrolled women, placentas and cord blood were collected at delivery, fatty acids were extracted and targeted lipid class analysis (triglyceride, TG; phosphatidylcholine, PC; lysophosphatidylcholine, LPC; eicosanoid) performed by LCMS. For this sub-analysis, participants were categorized as FGR (Fenton birth weight, BW ≤ 5%) or SGA “controls” (Fenton BW > 5%). FGRs (n = 8) delivered 1 week earlier (p = 0.04), were 29% smaller (p = 0.002), and had 133% higher UA pulsatility index (PI, p = 0.02) than SGAs (n = 12). FGR plasma TG, free arachidonic acid (AA), and several eicosanoids were increased (p < 0.05); docosahexaenoic acid (DHA)-LPC was decreased (p < 0.01). Plasma TG correlated inversely with BW (p < 0.05). Plasma EET, non-esterified AA, and DHA correlated inversely with BW and directly with UA PI (p < 0.05). Placental DHA-PC and AA-PC correlated directly with MCA PI (p < 0.05). In fetuses initially referred for inadequate fetal growth (EFW < 10%), those with BW ≤ 5% demonstrated distinctly different cord plasma lipid profiles than those with BW > 5%, which correlated with Doppler PIs. This provides new insights into fetal lipidomic response to the FGR in utero environment. The impact of these changes on specific processes of growth and development (particularly fetal brain) have not been elucidated, but the relationship with Doppler PI may provide additional context for FGR surveillance, and a more targeted approach to nutritional management of these infants.

The association between circulating docosahexaenoic acid and lung cancer: A Mendelian randomization study

Lung cancer is a malignant tumor with a high incidence, it is vital to identify modifiable and avoidable risk factors for primary prevention, which can significantly lower the risk of cancer by preventing exposure to hazards and altering risky behavior. Some observational studies suggest that an increase in docosahexaenoic acid (DHA) consumption can reduce lung cancer risk. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To evaluate the link between DHA and lung cancer, we have undertaken this analysis to examine the causal association between DHA and the risk of lung cancer using a two-sample Mendelian randomization (MR) framework. We performed a two-sample MR analysis to evaluate the causal effect of plasma DHA levels on lung cancer risk. For the exposure data, we extracted genetic variants as instrumental variables (IVs) that are strongly associated with DHA from a large-scale genome-wide association study (GWAS). We obtained the corresponding effect estimates for IVs on the risk of lung cancer with 11,348 cases and 15,861 controls. Finally, we applied Mendelian randomization analysis to obtain preliminary MR results and performed sensitivity analyses to verify the robustness of our results. According to the primary MR estimates and further sensitivity analyses, a higher serum DHA level was associated with a higher risk of lung cancer [OR=1.159, 95% CI (1.04-1.30), P=0.01]. For lung adenocarcinoma, the results also showed a close correlation between the DHA level and lung adenocarcinoma [OR=1.277, 95% CI (1.09-1.50), P=0.003], but it was not statistically significant for squamous cell carcinoma [OR=1.071, 95% CI (0.89-1.29), P=0.467]. Our study revealed that plasma DHA is positively associated with the risk of lung cancer overall, especially for lung adenocarcinoma. This study provides new information to develop dietary guidelines for primary lung cancer prevention.

Randomized controlled trial of early arachidonic acid and docosahexaenoic acid enteral supplementation in very preterm infants.

ObjectiveTo evaluate changes in blood long-chain polyunsaturated fatty acid (LCPUFA) and oxylipin concentrations in very preterm infants from birth to 36 weeks’ postmenstrual age (WPA) after providing an emulsified arachidonic acid (ARA):docosahexaenoic acid (DHA) supplement at two different concentrations.Study designThis prospective, randomized trial assigned infants to receive a supplement (1) 80:40 group (80 mg/kg/day ARA and 40 mg/kg/day DHA, n = 9) or (2) 120:60 group (120 mg/kg/day ARA and 60 mg/kg/day DHA, n = 9). Infants received supplement daily from birth until 36 WPA. At baseline, 21 days of life and 36 WPA, the LCPUFAs were measured in plasma by gas chromatography/mass spectrophotometry. Additionally, LCPUFAs and oxylipins were analyzed in whole blood by ultra-high-performance liquid chromatography-tandem mass spectrometry. Furthermore, a sample of oral mucosa was obtained to analyze single-nucleotide polymorphism located in the FADS1 gene by PCR.ResultsGestational age was similar between groups (80:40 = 28+6 [27+3; 30+3] completed weeks+days; 120:60 = 29+6 [27+3; 30+5] completed weeks+days, p = 0.83). At 36 WPA, the change in plasma ARA was significantly different between groups (80:40 group = 0.15 [−0.67; 0.69] %nmol, 120:60 = 1.68 [1.38; 3.16] %nmol, p = 0.031). In whole blood, the levels of ARA-derived oxylipins (5-, 8-, 9-, 11-, 15-HETE and 8,9-EET) and EPA-derived oxylipins (18-HEPE) significantly increase from baseline to 36 WPA in the 120:60 group than the 80:40 group.ConclusionSupplementation at high doses (120:60 mg/kg/day) increased levels of ARA, and EPA- and ARA-derived oxylipins compared to low doses (80:40 mg/kg/day). Differences were detected in EPA metabolites without a significant increase in plasma DHA.

Docosahexaenoic Acid as the Bidirectional Biomarker of Dietary and Metabolic Risk Patterns in Chinese Children: A Comparison with Plasma and Erythrocyte.

Objective: The present study aims to measure docosahexaenoic acid (DHA) in both the plasma and erythrocyte of a child population and compares them with respect to their associations with dietary and metabolic risk patterns. Methods: A cross-sectional study was conducted, and a total of 435 children ages 5–7 years old were recruited. Diet information was collected using a food frequency questionnaire (FFQ). The physical indicators, blood pressure, and glycolipid metabolic indicators were determined. The plasma and erythrocyte DHA were analyzed using a gas chromatography mass spectrometer. Principal component analysis was used to identify dietary and metabolic risk patterns. Multivariate regression analyses were used to investigate the associations of DHA status with dietary and metabolic risk patterns. Results: A significant correlation between plasma and the erythrocyte DHA concentration was found (r = 0.232, p < 0.001). A diversified dietary pattern characterized that a high intake of diversified foods had a positive association with the plasma DHA level (β = 0.145, 95% CI: 0.045~0.244, p = 0.004). Children of obesity risk patterns with a high weight, pelvis breadth, BMI, upper arm circumference, and chest circumference had lower plasma DHA concentrations (OR = 0.873, 95% CI: 0.786~0.969, p = 0.011). Children with higher plasma and erythrocyte DHA concentrations were adhered to blood lipid risk patterns with high CHOL and LDL-C levels. The plasma DHA (OR = 1.271, 95% CI: 1.142~1.415, p < 0.001) had a stronger association with a blood lipid risk pattern than erythrocyte (OR = 1.043, 95% CI: 1.002~1.086, p = 0.040). Conclusions: The diversified dietary pattern had a higher plasma DHA concentration. Lower levels of plasma DHA were positively associated with obesity in children. DHA in plasma appears to be more strongly associated with blood lipid metabolism than erythrocyte. Plasma DHA may be a more sensitive bidirectional biomarker to evaluate the recently comprehensive diet intake and metabolic risk of children.

Cytochrome P450 oxidase 2J inhibition suppresses choroidal neovascularization in mice

IntroductionChoroidal neovascularization (CNV) in age-related macular degeneration (AMD) leads to blindness. It has been widely reported that increased intake of ω−3 long-chain polyunsaturated fatty acids (LCPUFA) diets reduce CNV. Of the three major pathways metabolizing ω−3 (and ω−6 LCPUFA), the cyclooxygenase and lipoxygenase pathways generally produce pro-angiogenic metabolites from ω−6 LCPUFA and anti-angiogenic ones from ω−3 LCPUFA. Howevehr, cytochrome P450 oxidase (CPY) 2C produces pro-angiogenic metabolites from both ω−6 and ω−3 LCPUFA. The effects of CYP2J2 products on ocular neovascularization are still unknown. Understanding how each metabolic pathway affects the protective effect of ω−3 LCPUFA on retinal neovascularization may lead to therapeutic interventions. ObjectivesTo investigate the effects of LCPUFA metabolites through CYP2J2 pathway and CYP2J2 regulation on CNV both in vivo and ex vivo. MethodsThe impact of CYP2J2 overexpression and inhibition on neovascularization in the laser-induced CNV mouse model was assessed. The plasma levels of CYP2J2 metabolites were measured by liquid chromatography and tandem mass spectroscopy. The choroidal explant sprouting assay was used to investigate the effects of CYP2J2 inhibition and specific LCPUFA CYP2J2 metabolites on angiogenesis ex vivo. ResultsCNV was exacerbated in Tie2-Cre CYP2J2-overexpressing mice and was associated with increased levels of plasma docosahexaenoic acids. Inhibiting CYP2J2 activity with flunarizine decreased CNV in both ω−6 and ω−3 LCPUFA-fed wild-type mice. In Tie2-Cre CYP2J2-overexpressing mice, flunarizine suppressed CNV by 33 % and 36 % in ω−6, ω−3 LCPUFA diets, respectively, and reduced plasma levels of CYP2J2 metabolites. The pro-angiogenic role of CYP2J2 was corroborated in the choroidal explant sprouting assay. Flunarizine attenuated ex vivo choroidal sprouting, and 19,20-EDP, a ω−3 LCPUFA CYP2J2 metabolite, increased sprouting. The combined inhibition of CYP2J2 with flunarizine and CYP2C8 with montelukast further enhanced CNV suppression via tumor necrosis factor-α suppression. ConclusionsCYP2J2 inhibition augmented the inhibitory effect of ω−3 LCPUFA on CNV. Flunarizine suppressed pathological choroidal angiogenesis, and co-treatment with montelukast inhibiting CYP2C8 further enhanced the effect. CYP2 inhibition might be a viable approach to suppress CNV in AMD.

Omega-3 fatty acids, subclinical atherosclerosis, and cardiovascular events: Implications for primary prevention

Background and aimsHigh-dose eicosapentaenoic acid (EPA) therapy was beneficial in high-risk patients without clinical cardiovascular disease (CVD). Whether higher plasma levels of EPA and docosahexaenoic acid (DHA) have similar benefits in those without subclinical CVD is unclear. We aim to evaluate the interplay between plasma omega-3 fatty acids and coronary artery calcium (CAC) in relation to CVD events. MethodsWe examined 6568 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with plasma EPA and DHA levels and CAC measured at baseline. The primary outcome was incident CVD events (myocardial infarction, angina, cardiac arrest, stroke, CVD death). Hazard ratios for the primary outcome were adjusted for potential confounder using Cox regression. ResultsMean ± SD age was 62.1 ± 10.2 years and 52.9% were females. The median follow-up time was 15.6 years. Higher loge(EPA) (adjusted hazard ratio, aHR = 0.83; 95% CI, 0.74–0.94) and loge(DHA) (aHR = 0.79; 95% CI, 0.66–0.96) were independently associated with fewer CVD events. The difference in absolute CVD event rates between lowest vs. highest EPA tertile increased at higher CAC levels. The adjusted HR for highest vs. lowest EPA tertile within CAC = 0 was 1.02 (95% CI, 0.72–1.46), CAC = 1–99 was 0.71 (95% CI, 0.51–0.99), and CAC≥100 was 0.67 (95% CI, 0.52–0.84). A similar association was seen in tertiles of DHA by CAC category. ConclusionsIn an ethnically diverse population free of clinical CVD, higher plasma omega-3 fatty acid levels were associated with fewer long-term CVD events. The absolute decrease in CVD events with higher omega-3 fatty acid levels was more apparent at higher CAC scores.

DHA status influences effects of B-vitamin supplementation on cognitive ageing: a post-hoc analysis of the B-proof trial

PurposeTrials aiming to lower homocysteine by B-vitamin supplementation have reported mixed results on slowing cognitive decline. We investigated if efficacy of B-vitamin supplementation is affected by baseline plasma omega-3 fatty acid levels.MethodsThis post-hoc analysis of the B-proof trial included 191 adults aged 65 years or older with baseline plasma total homocysteine ≥ 12 μmol/L, randomly assigned to 400 µg folic acid and 500 µg vitamin B12 or placebo daily for 2 years. Global and domain-specific cognitive functioning were assessed at baseline and after 2 years. The effect of B-vitamin supplementation was analyzed according to tertiles of baseline plasma omega-3 fatty acids concentrations combined, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) individually using multiple linear regression analyses.ResultsThe mean ± SD age of the participants was 71.6 ± 5.9 years and median [IQR] Mini-Mental State Examination was 29 [28–30]. The treatment effect of B-vitamins on global cognition was larger in participants in the high compared to the middle DHA tertile (difference in z-score, mean ± SE 0.22 ± 0.10, p = 0.03). There was no significant interaction between B-vitamin supplementation and combined omega-3 fatty acid (p = 0.49) and EPA (p = 0.99) tertiles. Similarly, the efficacy of B-vitamin treatment on domain-specific cognitive functioning did not link to omega-3 fatty acid, DHA, or EPA plasma levels.ConclusionThis post-hoc analysis indicated that efficacy of B-vitamin supplementation in slowing cognitive decline relates to DHA status, with individuals with higher plasma DHA levels benefitting more from vitamin B12 and folic acid use. The results support earlier observations that positive effects of B-vitamins in cognitive ageing may be subgroup-specific.Trial registration: Registered at clinicaltrials.gov (NCT00696514) on June 12, 2008.

Effects of Fish Oil on Biomarkers of Axonal Injury and Inflammation in American Football Players: A Placebo-Controlled Randomized Controlled Trial.

There are limited studies on neuroprotection from repeated subconcussive head impacts (RSHI) following docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) supplementation in contact sports athletes. We performed a randomized, placebo-controlled, double-blinded, parallel-group design trial to determine the impact of 26 weeks of DHA+EPA supplementation (n = 12) vs. placebo (high-oleic safflower oil) (n = 17) on serum concentrations of neurofilament light (NfL), a biomarker of axonal injury, and inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)) in National Collegiate Athletic Association Division I American football athletes. DHA+EPA supplementation increased (p < 0.01) plasma DHA and EPA concentrations throughout the treatment period. NfL concentrations increased from baseline to week 26 in both groups (treatment (<0.001); placebo (p < 0.05)), with starting players (vs. non-starters) showing significant higher circulating concentrations at week 26 (p < 0.01). Fish oil (DHA+EPA) supplementation did not mitigate the adverse effects of RSHI, as measured by NfL levels; however, participants with the highest plasma DHA+EPA concentrations tended to have lower NfL levels. DHA+EPA supplementation had no effects on inflammatory cytokine levels at any of the timepoints tested. These findings emphasize the need for effective strategies to protect American football participants from the effects of RSHI.

Association of Prepregnancy Obesity and Remodeled Maternal-Fetal Plasma Fatty Acid Profiles.

BackgroundFatty acids, especially polyunsaturated fatty acid (PUFA), are found abundantly in the brain and are fundamental for a fetus's growth. The fatty acid profiles of mothers and fetuses may be affected by maternal prepregnancy body mass index (pre-BMI), thus affecting fetal growth and development.MethodsA total of 103 mother-fetus pairs were divided into overweight/obese (OW, n = 26), normal weight (NW, n = 60), and underweight (UW, n = 17) groups according to pre-BMI. Fatty acid profiles in maternal and umbilical cord plasma were analyzed by gas chromatography.ResultsThe infant birth BMI z-score of the OW group was higher than that of the NW and UW groups (p < 0.05). The OW mothers had significantly higher plasma n-6 PUFA and n-6/n-3, but lower docosahexaenoic acid (DHA) and n-3 PUFA (p < 0.05). In cord plasma, the proportions of DHA and n-3 PUFA were lower in the OW group (p < 0.05), whereas the n-6/n-3 ratio was higher in the OW group (p < 0.05). The pre-BMI was negatively correlated with cord plasma DHA in all subjects (r = −0.303, p = 0.002), and the same negative correlation can be observed in the OW group (r = −0.561, p = 0.004), but not in the NW and UW groups (p > 0.05). The pre-BMI was positively correlated with cord plasma n-6/n-3 in all subjects (r = 0.325, p = 0.001), and the same positive correlation can be found in the OW group (r = 0.558, p = 0.004), but not in NW and UW groups (p > 0.05).ConclusionsMaternal pre-BMI was associated with the maternal-fetal plasma fatty acid profiles, whereas the adverse fatty acid profiles are more noticeable in the prepregnancy OW mothers.

Preventive treatment with fish oil facilitates the antidepressant-like effect of antidepressant drugs in type-1 diabetes mellitus rats: Implication of serotonergic system

Treating depression associated with type-1 diabetesmellitus(T1DM) is a major clinical challenge. Fish oil (FO), composed mostly of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been pointed out as quite promising for the treatment of depression given its neuroprotective property. Although DHA and EPA exert several physiological actions, DHA is known to play a critical role in postnatal brain development. This study aimed to investigate the effect of preventive treatment with FO (with more DHA in the composition) alone or associated with antidepressant drugs on depression-like behaviors and brain monoamines levels of juvenile induced-T1DM rats. Thus, prepubescent rats were submitted to a prolonged treatment with vehicle (VEH) or FO (50% of DHA and 20% EPA) starting 4 weeks before the induction of experimental T1DM (on day 28) by streptozotocin. When combined, the treatment with vehicle, fluoxetine (FLX, a selective serotonin reuptake inhibitor) or imipramine (IMI, a tricyclic antidepressant) started at week 6 (day 42) and lasted for 2 weeks (until day 56). The behavioral tests were conducted on days 55 and 56, followed by hippocampal and prefrontal cortex dissection for neurochemical analyses. Our results showed that induced-T1DM rats pretreated with FO showed a significant increase of EPA and DHA in plasma, indicative of an increase in the systemic availability of these acids. As previously observed, induced-T1DM rats presented increased immobility and decreased swimming and climbing frequencies in the modified forced swimming test, indicative of depressive-like behavior. Only the combined treatment – FO plus antidepressants (FLX or IMI – both in the highest dose) - was able to induce a significant improvement of depressive-like behaviors. Here, it is noteworthy that swimming behavior has been associated with an increase in serotonergic neurotransmission. Interestingly, our data showed that the combined treatment (FO + antidepressants - including the ineffective dose of FLX) was able to increase the swimming of animals more significantly compared to animals not pretreated with FO. In addition, confirming these assumptions, the decreased 5-HT levels in the hippocampus from induced-T1DM rats were increased after treatment with FLX (highest dose) or IMI (both doses), being this increase more pronounced in animal pretreated with FO. Intriguingly, in these animals pretreated with FO, the ineffective dose of FLX in association with FO was able to increase the levels of 5-HT. The decreased hippocampal levels of noradrenaline were increased only after IMI treatment, not being influenced by FO pretreatment. In conclusion, ours results pointed out that the choice of the DHA/EPA ratio may be an important factor to be considered for the FO antidepressant-like effectper se,but the FO treatment in this composition associated with the antidepressant drugs - especially that ones that increase preferentially the availability of 5-HT -, may represent a better alternative of treatment to individuals with T1DM-associated depression.

Interactions between a polygenic risk score for plasma docosahexaenoic fatty acid concentration, eating behaviour, and body composition in children.

The relationship between eating behaviour and current body weight has been described. However little is known about the effect of polyunsaturated fatty acids (PUFA) in this relationship. Genetic contribution to a certain condition is derived from a combination of small effects from many genetic variants, and polygenic risk scores (PRS) summarize these effects. A PRS based on a GWAS for plasma docosahexaenoic fatty acid (DHA) has been created, based on SNPs from 9 genes. To analyze the interaction between the PRS for plasma DHA concentration, body composition and eating behaviour (using the Children Eating Behaviour Questionnaire) in childhood. We analyzed a subsample of children from the Maternal, Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort with PRS and measurements of eating behaviour performed at 4 years of age (n = 210), 6 y (n = 177), and body fat determined by bioelectric impedance at 4 y and 6 y or by air displacement plethysmography and dual-energy X-ray absorptiometry at 8 y (n = 42 and n = 37). PRS was based on the GWAS from Lemaitre et al. 2011 (p threshold = p < 5*10-6), and a median split created low and high PRS groups (high PRS = higher DHA level). In ALSPAC children, we observed an association between PRS and plasma DHA concentration (β = 0.100, p < 0.01) and proportion (β = 0.107, p < 0.01). In MAVAN, there were interactions between PRS and body fat on pro-intake scores in childhood, in which low PRS and higher body fat were linked to altered behaviour. There were also interactions between PRS and pro-intake scores early in childhood on body fat later in childhood, suggesting that the genetic profile and eating behaviour influence the development of adiposity at later ages. A lower PRS (lower plasma PUFA) can be a risk factor for developing higher body fat associated with non-adaptive eating behaviour in childhood; it is possible that the higher PRS (higher plasma PUFA) is a protective feature.

Entorhinal thickness: A marker of DHA supplementation efficacy?

AbstractBackgroundThe entorhinal cortex (ERC) area in the brain is affected early in AD, particularly among APOE4 carriers. We previously reported a positive association between plasma phospholipid docosahexaenoic acid (DHA) levels and the ERC thickness in the Aging Brain Program. We hypothesize that increases in plasma DHA after high‐dose DHA supplementation protects against thinning of the ERC when started before cognitive impairment including in APOE4 carriers, and that ERC thickness can be a useful marker for DHA supplementation efficacy.MethodWe examined the effect of DHA treatment and association of plasma DHA species on the changes in the ERC area in the DHA Brain Delivery Pilot Trial (NCT02541929). T1‐weighted MRI scans were collected at 3T and FreeSurfer software was used to segment the ERC thickness. Total DHA, DHA in phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and phosphatidylethanolamine (PE) were measured in plasma together with Red blood cell (RBC) DHA levels before and after randomization to 2 grams of triglyceride DHA per day vs placebo over 6 months (n=28). Participants were all cognitively normal, consumed less than 200 mg of DHA per day, and were stratified by APOE4 genotype before randomization.ResultDHA treatment, adjusted for APOE4, was associated with a significant increase in ERC area thickness compared with placebo (mean group difference in ERC change (95% CI) 0.161 (0.003, 0.319), p=0.046). Among DHA subspecies measured, greater increase in plasma PC DHA levels after supplementation was significantly correlated with greater ERC area (mean ERC change per SD of PC DHA=0.103, p=0.011). The association persisted after adjusting for APOE4 status (mean ERC change per SD of PC DHA=0.109, p=0.007), indicating that the effect was independent of APOE4 status.ConclusionThese preliminary findings support a protective effect of high dose DHA in preserving the ERC thickness, including among APOE4 carriers. This finding supports early intervention, before the onset of cognitive impairment, with high dose DHA supplementation in individuals at risk of cognitive decline. PREVENTE4 trial (NCT03613844) is ongoing to help understand whether high dose DHA can prevent cognitive decline in individuals at increased risk of AD.HNY is supported by AA NIRG‐15‐361854, R01AG054434, R21AG056518, ADDF GC‐201711‐2014197.

Docosahexaenoic Acid and Eicosapentaenoic Acid Intakes Modulate the Association of FADS2 Gene Polymorphism rs526126 with Plasma Free Docosahexaenoic Acid Levels in Overweight Children

Polyunsaturated fatty acids are involved in a wide variety of biological functions. Linoleic acid and alpha-linolenic acid are two essential fatty acids that the body cannot synthesize. The conversion rates in the body depend on FADS2 genetic variants. Certain variations in this gene are directly responsible for the low levels and poor conversion efficiency of the delta-6 desaturase enzyme, resulting in low circulating levels of docosahexaenoic acid. In this study, we evaluated the impact of the rs526126 FADS2 gene polymorphism on fatty acid levels in a group of two hundred children (n = 95 males, n = 105 females) aged 7–18 years, with obesity defined by BMI &gt; +2 SD. Fatty acid quantification was performed by LC-MS/MS while genotyping for genetic variants was performed using a custom-made hotspot sequencing panel of 55 SNPs. Our results suggest that rs526126 FADS2 gene polymorphism specifically impacts the plasma levels of free n-3 polyunsaturated fatty acids. Finally, the presence of the minor allele G of rs526126 could have beneficial effects, as it was associated with higher levels of free docosahexaenoic acid in plasma, especially in children with low n-3 intakes.

The ALGOVUE Clinical Trial: Effects of the Daily Consumption of Eggs Enriched with Lutein and Docosahexaenoic Acid on Plasma Composition and Macular Pigment Optical Density

Background. Carotenoids and docosahexaenoic acid (DHA) were identified as essential components for eye health and are both naturally present in eggs. Objective. We aimed to evaluate the effect of the daily consumption of two eggs enriched with lutein/zeaxanthin and DHA on macular pigment optical density (MPOD) and on circulating xanthophyll and fatty acid concentrations in healthy participants. Methods. Ninety-nine healthy volunteers consumed either two standard eggs or two enriched eggs per day for 4 months. MPOD was measured at baseline (V0) and at follow-up (V4) using a modified confocal scanning laser ophthalmoscope (primary outcome). Blood samples were collected to determine total plasma and lipoprotein fatty acids and lutein/zeaxanthin compositions at V0 and V4 (secondary outcomes). Results. A slight but significant increase in MPOD was observed for all study participants consuming two eggs per day for 4 months at all eccentricities (0.5°, 1°, 2°, and 4°). Plasma and lipoprotein lutein, zeaxanthin, and DHA concentrations significantly increased in both groups but were greater in the enriched group (for the enriched group (V0 vs. V4): lutein, 167 vs. 369 ng/mL; zeaxanthin, 17.7 vs. 29.2 ng/mL; DHA, 1.89 vs. 2.56% of total fatty acids). Interestingly, lutein from high-density lipoprotein (HDL) was strongly correlated with MPOD at 0.5 and 1° eccentricities (rho = 0.385, p = 0.008, and rho = 0.461, p = 0.001, respectively). Conclusions. MPOD was slightly increased in both groups. Lutein, zeaxanthin, and DHA plasma concentrations were strongly enhanced in the enriched group compared with the standard group. A significant correlation was found between MPOD level and lutein concentration in HDL.

Blood fatty acid analysis reveals similar n-3 fatty acid composition in non-pregnant and pregnant women and their neonates in an Israeli pilot study

Maternal docosahexaenoic acid (DHA) is required during pregnancy to supply for normal fetal growth and development. This pilot study aimed to assess the unknown fatty acid (FA) composition in a cohort of non-pregnant and pregnant Israeli women at term and their offspring on a normal diet without n-3 FA supplementation. The fatty acid profile, analyzed using gas chromatography, showed significantly higher plasma monounsaturated (MUFA) and lower n-6 FA percent distribution with similar n-3 index, in pregnant compared to non-pregnant women. RBC exhibited significantly higher MUFA with similar n-3 index, in pregnant compared to non-pregnant women. N-3 FA significantly correlated between neonates’ plasma, with higher n-3 index, and pregnant women's DHA. Conclusion: DHA levels in non-pregnant and pregnant Israeli women at term were comparable and the DHA in pregnant women's plasma positively correlated with their neonate's level, suggesting an efficient mother-fetus FA transfer and/or fetal fatty acid metabolism to longer FA products.

Adiponectin agonist treatment in diabetic pregnant rats.

Gestational diabetes mellitus (GDM) reduces maternal adiponectin and docosahexaenoic acid (DHA) materno-fetal transfer, which may have negative consequences for the offspring. Our aim was to evaluate the effects of the administration of a novel adiponectin agonist (AdipoRon) to GDM rats on the long-term consequences in glycaemia and fatty acids (FA) profile in the offspring. Pregnant rats were randomized to three groups: GDM rats (GDM, n = 8), GDM rats treated with AdipoRon (GDM + ADI, n = 9), and control rats (n = 10). Diabetes was induced with streptozotocin (50 mg/kg) on day 12 of gestation. GDM+ADI received 50 mg/kg/day AdipoRon from day 14 until delivery. Glycaemia and FA profile were determined in mothers and adult offspring (12 weeks old). AdipoRon tended to reduce fasting glucose in diabetic mothers. Diabetic rats presented the foetus with intrauterine growth restriction and higher adiposity, which tried to be counteracted by AdipoRon. In the adult offspring, both GDM + ADI and control animals showed better glucose recovery after oral glucose overload with respect to GDM. DHA in offspring plasma was significantly reduced in both GDM and GDM + ADI compared to controls (P = 0.043). Nevertheless, n-6/n-3 polyunsaturated FA (PUFA) ratio improved in plasma of GDM + ADI adult offspring (GDM: 14.83 ± 0.85a%; GDM + ADI: 11.49 ± 0.58b%; control: 10.03 ± 1.22b%, P = 0.034). Inflammatory markers and oxidative stress were reduced in the adult offspring of AdipoRon-treated mothers. In conclusion, AdipoRon administration to pregnant diabetic rats improved glycaemia in the mothers and long-term glucose tolerance in the offspring. In addition, it tended to reduce excessive foetal fat accumulation and improved n-6/n-3 PUFA ratio significantly in offspring at the adult state.