Omega 3 fatty acids and GPR120

Human loss-of-function gene variants in GPR120 have recently been identified that confer increased risk for obesity and metabolic syndrome. In addition, GPR120 KO mice develop obesity, increased inflammation, and insulin resistance, consistent with a role for GPR120 signaling in the metabolic syndrome and diabetes mellitus.     

Diacylglycerols containing Omega 3 and Omega 6 fatty acids bind to RasGRP and modulate MAP kinase activation

We elucidated the effects of different diacylglycerols (DAGs), i.e. 1-stearoyl-2-arachidonoyl-sn-glycerol (SAG), 1-stearoyl-2-docosahexaenoyl-sn-glycerol (SDG), and 1-stearoyl-2-eicosapentaenoyl-sn-glycerol (SEG), on [3H]PDBu binding to RasGRP. The competition studies with these DAGs on [3H]PDBu binding to RasGRP revealed different Ki values for these DAG molecular species. Furthermore, we transfected human Jurkat T cells by a plasmid containing RasGRP and assessed the implication of endogenous DAGs on activation of MAP kinases ERK1/ERK2, induced by phorbol-12-myristate-13-acetate (PMA). In control cells, GF109203X, a protein kinase C inhibitor, inhibited ERK1/ERK2 activation. However, this agent curtailed but failed to completely diminish ERK1/ERK2 phosphorylation in RasGRP-overexpressing cells, though calphostin C, a DAG binding inhibitor, suppressed the phosphorylation of MAP kinases in these cells. In cells incubated with arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), PMA induced the production of endogenous DAGs containing these fatty acids, respectively: DAG-AA, DAG-DHA, and DAG-EPA. The inhibition of production of DAG-AA and DAG-DHA significantly inhibited MAP kinase activation in RasGRP overexpressing, but not in control, cells. Our study demonstrates that three DAG molecular species bind to RasGRP, but only DAG-AA and DAG-DHA participate in the modulation of RasGRP-mediated activation of MAP kinases in Jurkat T cells.     

The effects of n-3 and n-6 polyunsaturated fatty acids on plasma lipids and fatty acids of treated phenylketonuric children

Dietary-treated phenylketonuric patients (PKUs) display low levels of long-chain polyunsaturated fatty acids (PUFA) in plasma lipids. In a 6-month clinical trial we observed a decrease of triglycerides and an increase of n-3 long-chain PUFA in plasma of PKUs supplemented with fish oil, while no major differences in respect to the baseline values were found in a group supplemented with blackcurrant oil. A more complete source of long-chain PUFA of both the n-6 and n-3 series should be investigated for dietary supplementation of PKU patients.     

A genome-wide association study of n-3 and n-6 plasma fatty acids in a Singaporean Chinese population

Polyunsaturated fatty acids (PUFAs) have a major impact on human health. Recent genome-wide association studies (GWAS) have identified several genetic loci that are associated with plasma levels of n-3 and n-6 PUFAs in primarily subjects of European ancestry. However, the relevance of these findings has not been evaluated extensively in other ethnic groups. The primary aim of this study was to evaluate for genetic loci associated with n-3 and n-6 PUFAs and to validate the role of recently identified index loci using data from a Singaporean Chinese population. Using a GWAS approach, we evaluated associations with plasma concentrations of three n-3 PUFAs [alphalinolenic acid (ALA), eicosapentaenoic acid and docosahexaenoic acid], four n-6 PUFAs [linoleic acid (LA), gammalinolenic acid, dihomogammalinolenic acid (DGLA) and arachidonic acid], and estimates of delta-5 desaturase and delta-6 desaturase activities among the participants (N = 1361) of the Singaporean Chinese Health Study. Our results reveal robust genome-wide associations (p value <5 × 10⁻⁸) with ALA, all four n-6 PUFAs, and delta-6 desaturase activity at the FADS1/FADS2 locus. We further replicated the associations between common index variants at the NTAN1/PDXDC1 locus and n-6 PUFAs LA and DGLA, and between the JMJD1C locus and n-6 PUFA LA (p value between 0.0490 and 9.88 × 10⁻⁴). These associations were independent of dietary intake of PUFAs. In aggregate, we show that genetic loci that influence plasma concentrations of n-3 and n-6 PUFAs are shared across different ethnic groups.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-015-0502-2) contains supplementary material, which is available to authorized users.     

{Omega}-3 and {omega}-6 polyunsaturated fatty acids block HERG channels

Dietary polyunsaturated fatty acids (PUFAs) have been reported to exhibit antiarrhythmic properties, which have been attributed to their availability to modulate Na⁺, Ca²⁺, and several K⁺ channels. However, their effects on human ether-a-go-go-related gene (HERG) channels are unknown. In this study we have analyzed the effects of arachidonic acid (AA, -6) and docosahexaenoic acid (DHA, -3) on HERG channels stably expressed in Chinese hamster ovary cells by using the whole cell patch-clamp technique. At 10 µM, AA and DHA blocked HERG channels, at the end of 5-s pulses to –10 mV, to a similar extent (37.7 ± 2.4% vs. 50.2 ± 8.1%, n = 7–10, P > 0.05). 5,6,11,14-Eicosatetrayenoic acid, a nonmetabolizable AA analog, induced effects similar to those of AA on HERG current. Both PUFAs shifted the midpoint of activation curves of HERG channels by –5.1 ± 1.8 mV (n = 10, P < 0.05) and –11.2 ± 1.1 mV (n = 7, P < 0.01). Also, AA and DHA shifted the midpoint of inactivation curves by +12.0 ± 3.9 mV (n = 4; P < 0.05) and +15.8 ± 4.3 mV (n = 4; P < 0.05), respectively. DHA and AA accelerated the deactivation kinetics and slowed the inactivation kinetics at potentials positive to +40 mV. Block induced by DHA, but not that produced by AA, was higher when measured after applying a pulse to –120 mV (IO). Finally, both AA and DHA induced a use-dependent inhibition of HERG channels. In summary, block induced by AA and DHA was time, voltage, and use dependent. The results obtained suggest that both PUFAs bind preferentially to the open state of the channel, although an interaction with inactivated HERG channels cannot be ruled out for AA. K⁺ channel; membrane currents; ion channels; arrhythmia; antiarrhythmics     

Omega oxidation of fatty acids and the pathway of 3-hydroxybutyric acid formation

Pathways followed by the carbons of long chain fatty acids in their conversion to 3-hydroxybutyric acid were traced and the contribution of ω-oxidation to fatty acid oxidation was determined in the cellular environment where ketone body formation occurs. 1-¹⁴C-, 2-¹⁴C-, and ω-¹⁴C-labeled fatty acids were injected into alloxan-induced diabetic rats in ketosis. 3-Hydroxybutyric acid was isolated from their urines and degraded. About 1.2 to 1.4 times as much ¹⁴C was found in carbon 1 as carbon 3 of 3-hydroxybutyric acid when the 1-¹⁴C-labeled fatty acids were injected and in carbon 2 as carbon 4 when the 2-¹⁴C-labeled fatty acids were injected. There was about 4 times as much incorporation into carbon 4 as carbon 2 of 3-hydroxybutyric acid formed from the ω-¹⁴C-labeled fatty acids. This means that 50% or more of the fatty acids were oxidized, so that the terminal two carbons of the fatty acids were converted to acetoacetyl-CoA without acetyl-CoA as an intermediate. Incorporation of ¹⁴C into carbons 1 and 2 of the hydroxybutyric acid reflects the distribution of ¹⁴C in acetyl-CoA. Incorporation into carbon 1 was very small when the ω-¹⁴C-labeled fatty acids were substrate. This means that ω-oxidation of fatty acids makes, at most, a small contribution to the formation of the acetyl-CoA pool from which acetoacetate is derived.     

Epidemiology of ADHD in Chilean children and adolescents

ADHD prevalence, associated factors, comorbidity and service use are reported for a sample of 1,558 children and adolescents, belonging to four provinces in Chile. The sample is weighted in each step for selection bias. Psychiatric disorders and impairment are assessed with computerized in-home DISC-IV interviews, and a questionnaire regarding socioeconomic and family variables and service use. Estimates of prevalence rates are obtained by means of STATA 11.0 software, with complex sample design. Multivariate logistic regression is used to determine which factors were the best predictors for mental disorders. Participation rate is 82.4 %. The prevalence of ADHD is 10 %, and the most prevalent subtype is the hyperactive/impulsive, with no gender differences. Both hyperactive/impulsive and combined subtypes are more prevalent in children 4–11 than in adolescents. The most prevalent comorbidities are anxiety disorders and oppositional disorder. Anxiety is the more prevalent comorbid disorder in girls and correlated with a combined subtype. Perception of good family functioning, adolescent age and school dropout have a negative association with ADHD diagnosis, while maltreatment shows a positive correlation. Over 50 % of children and adolescents diagnosed with ADHD have used services in the last year. This is the first comprehensive community study of psychiatric disorders in children and adolescents in a South American country. It yields information for child and adolescent mental health programmes in Chile and contributes to cross-cultural epidemiological research.     

Polyunsaturated fatty acids in plasma and erythrocyte membrane lipids of diabetic children

While insulin is a potent activator of essential fatty acid metabolism, portal hypoinsulinemia is common in Type 1 diabetes. Fatty acids were determined by high-resolution capillary gas-liquid chromatography in plasma and erythrocyte membrane lipids in diabetic children (n = 40) and in age-matched healthy controls (n = 40). In plasma phospholipids, values of linoleic acid (23.00 [2.35] vs. 18.13 [2.54], % by wt, median [range from the first to the third quartile], P<0.000l) and alpha-linolenic acid (0.12 [0.06] vs. 0.07 [0.07], P<0.05) were significantly higher in diabetic children than in controls. In contrast, values of arachidonic acid (10.73 [2.34] vs. 11.53 [2.50], P<0.05) and docosahexaenoic acid (2.23 [0.63] vs. 2.77 [0.98], P<0.01) were significantly lower in diabetic children than in controls. Reduced availability of long-chain polyunsaturates in diabetic children suggests that an enhanced dietary supply of long-chain polyunsaturates may be beneficial.     

Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools

BackgroundDietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations.ObjectiveTo evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache.DesignSecondary analysis of a randomized trial. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3–L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet.ResultsCompared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3–L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations.ConclusionDietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA.     

Fatty acid-related phylogeny of myxobacteria as an approach to discover polyunsaturated omega-3/6 Fatty acids

In an analysis of 47 aerobic myxobacterial strains, representing 19 genera in suborders Cystobacterineae, Nannocystineae, Sorangiineae, and a novel isolate, "Aetherobacter" SBSr008, an enormously diverse array of fatty acids (FAs) was found. The distribution of straight-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) supports the reported clustering of strains in the phylogenetic tree based on 16S rRNA genes. This finding additionally allows the prediction and assignment of the novel isolate SBSr008 into its corresponding taxon. Sorangiineae predominantly contains larger amounts of SCFA (57 to 84%) than BCFA. On the other hand, Cystobacterineae exhibit significant BCFA content (53 to 90%), with the exception of the genus Stigmatella. In Nannocystineae, the ratio of BCFA and SCFA seems dependent on the taxonomic clade. Myxobacteria could also be identified and classified by using their specific and predominant FAs as biomarkers. Nannocystineae is remarkably unique among the suborders for its absence of hydroxy FAs. After the identification of arachidonic (AA) FA in Phaselicystidaceae, eight additional polyunsaturated fatty acids (PUFAs) belonging to the omega-6 and omega-3 families were discovered. Here we present a comprehensive report of FAs found in aerobic myxobacteria. Gliding bacteria belonging to Flexibacter and Herpetosiphon were chosen for comparative analysis to determine their FA profiles in relation to the myxobacteria.     

Effect of n-3 and n-6 fatty acids on hepatic microsomal lipid metabolism: a time course study

The present study examines the time dependent effects of n-6 and n-3 polyunsaturated fatty acids on liver microsomal lipid metabolism in FVB mice fed a diet supplemented with a mixture of free fatty acids (mainly 18:3n-6 and 20:5n-3) at 25 mg/g diet. Significant changes in the fatty acid composition of total liver and microsomal lipids were observed after 7 days on the diets. Thereafter, some animals remained on the same diet while others were fed a diet supplemented with hydrogenated coconut oil (HCO). With the exception of 20:5n-3 which showed a slower recovery, establishment of the HCO pattern was rapid indicating that the diet-induced changes could be easily reversed. The unsaturation index, the cholesterol/phospholipid ratio and the microviscosity of the microsomal membranes were not affected by these dietary manipulations. Unsaturated fatty acid supplementation reduced the activity of ⁹ desaturase by 50%. Feeding the HCO diet to mice previously fed the EPA/GLA diet led to a progressive increase in ⁹ desaturase activity, reaching 80% of the day zero values after 14 days. The monoene content of hepatic total lipids reflected, in most cases, the changes in enzyme activity. This study shows that a low dose of a n-3 and n-6 free fatty acid mixture increases the quantities of members of the n-3 family, without loss of n-6 fatty acids in microsomal membranes and modifies the activity of ⁹ desaturase without altering the microsome physicochemical parameters.     

The effect of altering the 20:5n-3 and 22:6n-3 content of a meal on the postprandial incorporation of n-3 polyunsaturated fatty acids into plasma triacylglycerol and non-esterified fatty acids in humans

Previous studies suggest that consuming meals containing large amounts of fish oil is associated with selective postprandial incorporation of 20:5n-3 and 22:6n-3 into plasma non-esterified fatty acids (NEFA). We investigated the effect of consuming meals containing different amounts of 20:5n-3 and 22:6n-3 comparable to dietary habits of western populations on the postprandial incorporation of 18:3n-3, 20:5n-3 and 22:6n-3 into plasma triacylglycerol (TAG) and NEFA over 6h in middle aged subjects. 20:5n-3 incorporation into plasma TAG was greater than 22:6n-3 irrespective of the test meal. Conversely, 22:6n-3 incorporation into plasma NEFA was greater than 20:5n-3, irrespective of the test meal. There was no effect of the amount of 20:5n-3+22:6n-3 in the test meal on the 18:3n-3 incorporation into plasma TAG or NEFA. These findings suggest differential metabolism of 20:5n-3 and 22:6n-3 in the postprandial period when consumed in amounts typical of western dietary habits.     

Red blood cell fatty acids are associated with depression in a case-control study of adolescents

IntroductionEpidemiological studies suggest that reduced intakes and/or blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with increased risk for depression in adults, but data on adolescents are scarce. The objective of this study was to determine whether red blood cell (RBC) levels of EPA+DHA (the omega-3 index) and/or the overall RBC fatty acid profile differ between depressed adolescents (cases) and non-depressed adolescents (controls).Patients and MethodsWe measured the RBC fatty acid composition of cases admitted to the hospital for depression (n=150) and compared it to that of controls (n=161).ResultsCases and controls had similar ages, gender proportions, and body mass index (BMI) distributions, but there was a significant difference in racial/ethnic composition due to differences in recruitment sites. The unadjusted odds ratio for case status was 0.72 (95% CI; 0.55–0.95) for a 1% absolute increase in the omega-3 index. A multivariable logistic regression model was used to determine which fatty acids were useful in classifying cases and controls; BMI, age, gender, and race/ethnicity were forced into the model. Seven fatty acids were selected (DHA, myristic, stearic, oleic, trans linoleic, trans palmitoleic, and alpha-linolenic acids) to optimize the model fit to the data. In the adjusted model, the odds ratio was 0.67 (95% CI; 0.49–0.93) for a 1 SD increase in DHA. Adding the seven fatty acid profile to the basic model increased the area under the ROC curve by 12.6% (7.5%–17.6%).Discussion and ConclusionThese findings support the hypothesis that adolescent depression is associated with a perturbed RBC fatty acid pattern which includes a reduced omega-3 index. Intervention studies with EPA and DHA should be conducted in this vulnerable population for which few, safe therapeutic options currently exist.     

Emotion recognition in children and adolescents with attention-deficit/hyperactivity disorder (ADHD)

Children with attention-deficit/hyperactivity disorder (ADHD) are impaired in social adaptation and display deficits in social competence. Deficient emotion recognition has been discussed to underlie these social problems. However, comorbid conduct problems have not been considered in the majority of studies conducted so far, and the influence of medication on emotion recognition has rarely been studied. Here, emotion recognition performance was assessed in children with ADHD without medication compared with children with ADHD under stimulant medication and a matched control group. In order to rule out confounding by externalizing symptoms, children with comorbid conduct problems were excluded. Video clips with neutral faces developing a basic emotion (happiness, sadness, disgust, fear and anger) were presented in order to assess emotion recognition. Results indicated between-group differences neither concerning the number of correctly identified emotions nor concerning reaction times and their standard deviations. Thus, we suggest that ADHD per se is not associated with deficits in emotion recognition.     

Dietary ratio of n-6 to n-3 polyunsaturated fatty acids and periodontal disease in community-based older Japanese: a 3-year follow-up study

The longitudinal relationship between dietary n-6 to n-3 PUFAs ratio and periodontal disease in 235 Japanese subjects for whom data were available for the years 2003-2006 was investigated. PUFAs intake was assessed at baseline with a brief-type self-administered diet history questionnaire. Full-mouth periodontal status, measured as the clinical attachment level (CAL), was recorded at baseline and once a year for 3 years. The number of teeth with a change in the loss of CAL ≥3 mm at any site over a year was calculated as ‘periodontal disease events’. Poisson regression analysis was conducted, with dietary n-6 to n-3 PUFAs ratio as the main predictor, to estimate its influence on periodontal disease events.A high dietary n-6 to n-3 PUFAs ratio was significantly associated with greater number of periodontal disease events. The findings suggest the dietary n-6 to n-3 PUFAs ratio is associated with periodontal disease among older Japanese.     

Project DyAdd: Fatty acids in adult dyslexia, ADHD, and their comorbid combination

In project DyAdd, we compared the fatty acid (FA) profiles of serum phospholipids in adults with attention deficit hyperactivity disorder (ADHD) (n=26), dyslexia (n=36), their comorbid combination (n=9), and healthy controls (n=36). FA proportions were analyzed in a 2×2 design with Bonferroni corrected post hoc comparisons. A questionnaire was used to assess dietary fat quality and use of supplements. Results showed that ADHD and dyslexia were not associated with total saturated FAs, monounsaturated FAs, or n-3 polyunsaturated FAs (PUFAs). However, those with ADHD had elevated proportions of total n-6 PUFAs (including γ-linolenic and adrenic acids) as compared to those without ADHD. Dyslexia was related to a higher proportion of monounsaturated nervonic acid and a higher ratio of n-6/n-3 PUFAs. Among females none of the associations were significant. However in males, all the original associations observed in all subjects remained and ADHD was associated with elevated nervonic acid and n-6/n-3 PUFA ratio like dyslexia. Controlling for poorly diagnosed reading difficulties, education, dietary fat quality, or use of FA supplements did not generally remove the originally observed associations.     

Non-alcoholic fatty liver disease severity and metabolic complications in obese children: impact of omega-3 fatty acids

Although n-3 polyunsaturated fatty acids (PUFA) revealed promising therapeutic results in non-alcoholic fatty liver disease (NAFLD), which is considered as the most prevalent cause of chronic hepatic disease, inconsistencies are calling for further confirmatory trials to demonstrate therapeutic efficacy and safety. The study, registered as NCT02201160 on www.clinicaltrials.gov, was designed to compare two groups of NAFLD with a different severity, and to evaluate the efficacy of n-3 PUFA supplementation. Twenty young male participants of French Canadian origin with NAFLD were enrolled and classified into moderate (mNAFLD) and severe (sNAFLD) fatty liver groups, according to transaminase levels, ultrasonography, NAFLD Activity Score and Fatty Liver Index (FLI). The sNAFLD patients were assigned to consume 2 g of n-3 PUFA for 6 months. sNAFLD patients displayed higher insulinemia, insulin resistance (IR), oxidative stress (OxS), systolic blood pressure and the risk lipid indicators of cardiovascular diseases. Supplementation of n-3 PUFA for 6 months resulted in a significant increase in concentrations of eicosapentaenoic and docosahexaenoic acids in red blood cells along with an attenuation of hepatic steatosis as reflected by the reduction of the FLI, ALT and ALT/AST ratio. Moreover, the n-3 PUFA improved the lipid profile and carotid intima-media thickness, while reducing metabolic and OxS markers as well as raising adiponectin. In conclusion, NAFLD severity was essentially related to IR. Treatment with n-3 PUFA has an evidently beneficial effect on liver steatosis and related metabolic abnormalities. Furthermore, the cross association of omega-3 index with cardiometabolic markers may serve as a predictor for cardiovascular risk disorders in NAFLD.     

The Kiddie-SADS allows a dimensional assessment of externalizing symptoms in ADHD children and adolescents

Objective of the study was the investigation of the psychometric properties of a scale derived from the Kiddie-SADS used for a dimensional assessment of externalizing symptoms in children and adolescents. The scale consists of 26 DSM-IV Kiddie-SADS items for attention deficit hyperactivity disorder (ADHD, 18 items) and oppositional defiant disorder (ODD, 8 items). Patients and their mothers were interviewed separately on the patients' symptoms during the last 2 weeks prior to interview. An ADHD-ODD sum score ranging between 0 and 26 was computed reflecting the number of fulfilled diagnostic criteria within the 2-week period under investigation. Interviews were videotaped and re-rated by an independent second rater. Additionally, mothers filled out two questionnaires on their children's symptoms (FBB-HKS, a German ADHD scale based on ICD-10 and DSM-IV criteria; strength and difficulties questionnaire, SDQ). We investigated 59 patients affected by AD(H)D according to DSM-IV recruited from our Department for Child and Adolescent Psychiatry (39 males, 20 females; mean age: M=9.66, SD=2.30). Inter-rater correlation regarding the ADHD-ODD scores was r=0.98 with no significant differences in mean sum scores between rater 1 and rater 2. Internal consistency of the ADHD-ODD scale was 0.85 (Cronbach's alpha). Item difficulties and discriminative power of the items also proved to be adequate. Convergent and discriminant validity were indicated by middle to high correlations with mother-ratings of the children's externalizing symptoms and a low correlation with ratings of internalizing symptoms. Factor analysis revealed a three-factor solution mainly covering inattentive, hyperactive and oppositional symptoms. In summary, ADHD and ODD sections of the Kiddie-SADS allow a reliable and valid dimensional assessment of externalizing symptoms in AD(H)D children and adolescents.