Early-life dietary long-chain polyunsaturated fatty acid consumption promotes immune function and reduces systemic and adipose inflammation in a sex-specific manner in obese Wistar rats.

The dose-responsiveness of plasma oxylipins to incremental dietary intake of arachidonic acid (20:4n-6; ARA) and docosahexaenoic acid (22:6n-3; DHA) was determined in piglets. Piglets randomly received one of six formulas (n = 8 per group) from days 3 to 27 postnatally. Diets contained incremental ARA or incremental DHA levels as follows (% fatty acid, ARA/DHA): (A1) 0.1/1.0; (A2) 0.53/1.0; (A3-D3) 0.69/1.0; (A4) 1.1/1.0; (D1) 0.66/0.33; and (D2) 0.67/0.62, resulting in incremental intake (g/kg BW/day) of ARA: 0.07 ± 0.01, 0.43 ± 0.03, 0.55 ± 0.03, and 0.82 ± 0.05 at constant DHA intake (0.82 ± 0.05), or incremental intake of DHA: 0.27 ± 0.02, 0.49 ± 0.03, and 0.81 ± 0.05 at constant ARA intake (0.54 ± 0.04). Plasma oxylipin concentrations and free plasma PUFA levels were determined at day 28 using LC-MS/MS. Incremental dietary ARA intake dose-dependently increased plasma ARA levels. In parallel, ARA intake dose-dependently increased ARA-derived diols 5,6- and 14,15-dihydroxyeicosatrienoic acid (DiHETrE) and linoleic acid-derived 12,13-dihydroxyoctadecenoic acid (DiHOME), downstream metabolites of cytochrome P450 expoxygenase (CYP). The ARA epoxide products from CYP are important in vascular homeostatic maintenance. Incremental DHA intake increased plasma DHA and most markedly raised the eicosapentaenoic acid (EPA) metabolite 17,18-dihydroxyeicosatetraenoic acid (DiHETE) and the DHA metabolite 19,20-dihydroxydocosapentaenoic acid (DiHDPE). In conclusion, increasing ARA and DHA intake dose-dependently influenced endogenous n-6 and n-3 oxylipin plasma concentrations in growing piglets, although the biological relevance of these findings remains to be determined.

Human milk contains n-3 and n-6 LCPUFA (long chain polyunsaturated fatty acids), which are absent from many infant formulas. During neonatal life, there is a rapid accretion of AA (arachidonic acid) and DHA (docosahexaenoic acid) in infant brain, DHA in retina and of AA in the whole body. The DHA status of breast-fed infants is higher than that of formula-fed infants when formulas do not contain LCPUFA. Studies report that visual acuity of breast-fed infants is better than that of formula-fed infants, but other studies do not find a difference. Cognitive development of breast-fed infants is generally better, but many sociocultural confounding factors may also contribute to these differences. The effect of dietary LCPUFA on FA status, immune function, visual, cognitive, and motor functions has been evaluated in preterm and term infants. Plasma and RBC FA status of infants fed formulas supplemented with both n-3 and n-6 LCPUFA was closer to the status of breast-fed infants than to that of infants fed formulas containing no LCPUFA. Adding n-3 LCPUFA to preterm-infant formulas led to initial beneficial effects on visual acuity. Few data are available on cognitive function, but it seems that in preterm infants, feeding n-3 LCPUFA improved visual attention and cognitive development compared with infants receiving no LCPUFA. Term infants need an exogenous supply of AA and DHA to achieve similar accretion of fatty acid in plasma and RBC (red blood cell) in comparison to breast-fed infants. Fewer than half of all studies have found beneficial effects of LCPUFA on visual, mental, or psychomotor functions. Improved developmental scores at 18 mo of age have been reported for infants fed both AA and DHA. Growth, body weight, and anthropometrics of preterm and term infants fed formulas providing both n-3 and n-6 LCPUFA fatty acids is similar in most studies to that of infants fed formulas containing no LCPUFA. A larger double-blind multicenter randomized study has recently demonstrated improved growth and developmental scores in a long-term feeding study of preterm infants. Collectively, the body of literature suggests that LCPUFA is important to the growth and development of infants. Thus, for preterm infants we recommend LCPUFA intakes in the range provided by feeding of human milk typical of mothers in Western countries. This range can be achieved by a combination of AA and DHA, providing an AA to DHA ratio of approximately 1.5 and a DHA content of as much as 0.4%. Preterm infants may benefit from slightly higher levels of these fatty acids than term infants. In long-term studies, feeding more than 0.2% DHA and 0.3% AA improved the status of these fatty acids for many weeks after DHA; AA was no longer present in the formula, enabling a DHA and AA status more similar to that of infants fed human milk. The addition of LCPUFA in infant formulas for term infants, with appropriate regard for quantitative and qualitative qualities, is safe and will enable the formula-fed infant to achieve the same blood LCPUFA status as that of the breast-fed infant.

We studied the long-chain conversion of [U-13C]alpha-linolenic acid (ALA) and linoleic acid (LA) and responses of erythrocyte phospholipid composition to variation in the dietary ratios of 18:3n-3 (ALA) and 18:2n-6 (LA) for 12 weeks in 38 moderately hyperlipidemic men. Diets were enriched with either flaxseed oil (FXO; 17 g/day ALA, n=21) or sunflower oil (SO; 17 g/day LA, n=17). The FXO diet induced increases in phospholipid ALA (>3-fold), 20:5n-3 [eicosapentaenoic acid (EPA), >2-fold], and 22:5n-3 [docosapentaenoic acid (DPA), 50%] but no change in 22:6n-3 [docosahexanoic acid (DHA)], LA, or 20:4n-6 [arachidonic acid (AA)]. The increases in EPA and DPA but not DHA were similar to those in subjects given the SO diet enriched with 3 g of EPA plus DHA from fish oil (n=19). The SO diet induced a small increase in LA but no change in AA. Long-chain conversion of [U-13C]ALA and [U-13C]LA, calculated from peak plasma 13C concentrations after simple modeling for tracer dilution in subsets from the FXO (n=6) and SO (n=5) diets, was similar but low for the two tracers (i.e., AA, 0.2%; EPA, 0.3%; and DPA, 0.02%) and varied directly with precursor concentrations and inversely with concentrations of fatty acids of the alternative series. [13C]DHA formation was very low (<0.01%) with no dietary influences.

Background: Dietary long chain polyunsaturated fatty acids (LCPUFA) such as arachidonic acid (ARA) and docosahexaenoic acid (DHA) play an important role in the development of the infant immune system. The role of LCPUFA in the T helper type 2 (Th2) biased immune system is unknown. We aimed to understand the effect of feeding LCPUFA during suckling and post-weaning on immune system development in Th2 bias Brown Norway rat offspring.Methods: Brown Norway dams were randomly assigned to nutritionally adequate maternal diet throughout the suckling period (0–3 weeks), namely, control diet (0% ARA, 0% DHA; n= 8) or ARA + DHA (0.45% ARA, 0.8% DHA; n = 10). At 3 weeks, offspring from each maternal diet group were randomized to either a control (0% ARA, 0% DHA; n = 19) or ARA+DHA post-weaning (0.5% ARA, 0.5% DHA; n = 18) diet. At 8 weeks, offspring were killed, and tissues were collected for immune cell function and fatty acid composition analyses.Results: ARA + DHA maternal diet resulted in higher (p < 0.05) DHA composition in breast milk (4×) without changing ARA levels. This resulted in more mature adaptive immune cells in spleen [T regulatory (Treg) cells and B cells], mesenteric lymph nodes (MLN, lower CD45RA+), and Peyer's patches (PP; higher IgG+, B cells) in the ARA+DHA group offspring at 8 weeks. ARA+DHA post-weaning diet (3–8 weeks) resulted in 2 × higher DHA in splenocyte phospholipids compared to control. This also resulted in higher Th1 cytokines, ~50% higher TNF-α and IFNγ, by PMAi stimulated splenocytes ex vivo, with no differences in Th2 cytokines (IL-4, IL-13, and IL-10) compared to controls.Conclusion: Feeding dams a diet higher in DHA during the suckling period resulted in adaptive immune cell maturation in offspring at 8 weeks. Providing ARA and DHA during the post-weaning period in a Th2 biased Brown Norway offspring model may support Th1 biased immune response development, which could be associated with a lower risk of developing atopic diseases.

Dietary supplements of olive oil (OO) or fish oil (FO) during the first (G1: day 1-60) or second half of gestation (G2: day 60 to term, day 115) were offered to pregnant sows. The proportion of fatty acids in milk and plasma were determined by gas chromatography. When supplements were given during G1, the proportions of oleic acid (OA) and arachidonic acid (AA) in the plasma were higher in the OO group than in the FO group, whereas docosahexaenoic acid (DHA) was higher in the latter group at day 56 of gestation. These differences in plasma DHA were still apparent at day 7 of lactation. Similarly, DHA was also higher in the colostrum and milk on days 3 and 21 of lactation and in the plasma of piglets from FO dams compared to the OO group, whereas AA was lower. When the FO supplement was given during G2, AA was lower and DHA higher in the plasma at day 105 of gestation and at day 7 of lactation compared with the OO group. Likewise, DHA was greater in FO than in OO animals during lactation in colostrum and in milk on days 3 and 21 of lactation, and in 3-day old suckling piglets plasma, whereas AA was lower in these animals. Thus, maternal adipose tissue plays an important role in the storage of dietary long-chain polyunsaturated fatty acids (LCPUFA) during G1. They are mobilized around parturition for milk synthesis, and an excess of dietary n-3 LCPUFA decreases the availability of AA in suckling newborns.

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are essential to meet LC-PUFA requirements of juvenile California Yellowtail (Seriola dorsalis)

The amount and distribution of [(13)C]docosahexaenoic acid (DHA) in plasma, platelet, and erythrocyte lipid classes were followed as a function of time (1 to 72 h) in young adults after ingestion of a single dose of [(13)C]DHA esterified in a phosphatidylcholine (PC), in using gas chromatography combustion;-isotope ratio mass spectrometry. [(13)C]DHA first appeared in plasma non-esterified fatty acids (NEFA) and triglycerides (TG), with a maximal appearance at 6 h and a further decline, then being delayed 3-fold compared to [(13)C]DHA ingested in triglycerides. Lysophosphatidylcholine (LPC) was also enriched in [(13)C]DHA, due mainly to earlier hepatic secretion, and plateaued at 6 h, whereas phosphatidylethanolamine (PE) and phosphatidylcholine (PC) containing [(13)C]DHA plateaued at 9 h. The labeling of erythrocyte and platelet phospholipids exhibited different kinetics, probably involving different metabolic pathways for [(13)C]DHA incorporation in cell membranes. Computation of the relative contribution of LPC and NEFA for delivery of [(13)C]DHA to blood cells showed that the supply to platelets occurred through NEFA. In contrast, [(13)C]DHA was carried by both LPC and NEFA to erythrocytes, which differs from what was previously been observed after intake of triglycerides labeled with [(13)C]DHA where LPC was the only source of [(13)C]DHA for erythrocytes. We conclude that the lipid form of ingested DHA affects markedly its kinetics and partly its metabolic fate.

Brain phospholipids are highly enriched in docosahexaenoic acid (DHA; 22:6n-3). Recent advances indicate that 22:6n-3 is released from brain phospholipids via the action of phospholipase A2 (PLA2) in response to several stimuli, including neurotransmission, where it then acts as a secondary messenger. Furthermore, it is now known that released 22:6n-3 is a substrate for several oxygenation enzymes whose products are potent signaling molecules. One emerging candidate PLA2 involved in the release of 22:6n-3 from brain phospholipids is the group VI calcium-independent phospholipase A2 (iPLA2). After a brief review of brain 22:6n-3 metabolism, cell culture and rodent studies facilitating the hypothesis that group VI iPLA2 releases 22:6n-3 from brain phospholipids are discussed. The identification of PLA2s involved in cleaving 22:6n-3 from brain phospholipids could lead to the development of novel therapeutics for brain disorders in which 22:6n-3 signaling is disordered.

Dietary long-chain polyunsaturated fatty acids are known to benefit infant development. After birth, human milk provides arachidonic, eicosapentaenoic, and docosahexaenoic acids to the infant. Endocannabinoids are endogenous lipid mediators derived from the long-chain polyunsaturated fatty acids. Although the roles and the mechanisms of action are not fully understood, previous researchers have suggested that endocannabinoids might play a role in infant feeding behavior. To assess (i) maternal dietary intake of long-chain polyunsaturated fatty acids and (ii) their relationship to concentrations of fatty acids and derived endocannabinoids in human milk. For this exploratory-longitudinal study, participants (N = 24) provided dietary intake data and milk samples. Fatty acids and derived endocannabinoids: Arachidonylethanolamide, arachidonoylglycerol, docosahexaenoyl glycerol, eicosapentaenoyl ethanolamide, and eicosapenaenoyl glycerol were identified in their milk by liquid chromatography-mass spectrometry and correlations to dietary fatty acids were assessed. Participants were not consuming recommended amounts of docosahexaenoic acid. Significant correlations (p ≤ .05) were only found between dietary docosahexaenoic and eicosapentaenoic acids and the concentrations of these in human milk. Moreover, only dietary docosahexaenoic acid was correlated (p = .031) with its corresponding endocannabinoid, docosahexaenoyl glycerol. To the best of our knowledge, this may be one of the first studies evaluating relationships between dietary long-chain polyunsaturated fatty acids and multiple endocannabinoids in human milk. Our findings suggest that endocannabinoid concentrations could be modulated by dietary precursors. Future research studies can be designed based on these data to better elucidate the roles of endocannabinoids in human milk for infant health and development.

ABSTRACTAging is associated with a gradual and progressive decline in skeletal muscle mass and strength known as sarcopenia, which has been attributed to chronic low-grade inflammation. Dietary long-chain polyunsaturated fatty acids (LC-PUFAs), including omega-6 arachidonic acid (ARA) and omega-3 docosahexaenoic acid (DHA), are precursors to bioactive lipid mediators that regulate the initiation, propagation, and active resolution of inflammation. While traditionally considered a pro-inflammatory and catabolic factor, the ARA-derived eicosanoid prostaglandin E2has recently emerged as a potential anti-sarcopenic molecule. DHA-derived specialized pro-resolving mediators may also act as immunomodulatory pro-regenerative molecules in muscle inflammaging. In the current study, we tested the effects of long-term dietary supplementation with either ARA or DHA on muscle health in aging mice. Twenty-two-month-old C57BL/6N mice were fed a control AIN-93M diet, or an AIN-93M diet supplemented with either ARA (0.48% w/w) or DHA (0.48% w/w) for 12 weeks. Both dietary interventions reduced total body weight, but only ARA reduced absolute fat mass and increased the percentage of lean mass. Despite these changes in body composition, ARA supplementation reduced absolute muscle strength and myofiber size. This functional decline was associated with increased neuromuscular junction fragmentation, elevated expression of pro-inflammatory cytokines/protein degradation markers, and suppressed ribosome biogenesis. In contrast, DHA uniquely reduced chronic inflammation of aged muscle and returned c-Myc expression to young levels but did not affect muscle mass or strength. These data demonstrate that long-term dietary intake of ARA and DHA have overall divergent effects on the structure and function of aging muscle.

Omega-3 Long-Chain Polyunsaturated Fatty Acids in Older Children

To review briefly the influence of dietary long-chain polyunsaturated fatty acids (LC-PUFA) on tissue composition and functionality in early infancy. Moreover, the influences of LC-PUFA sources on plasma composition as well as the effects of these fatty acids on intestinal repair after malnutrition are discussed. Human milk not only supplies essential fatty acids but also contains up to 2% of the total fatty acids as LC-PUFA, of which arachidonic acid (AA) and docosahexaenoic acid (DHA) are considered the most important. Plasma and erythrocyte levels of both AA and DHA are decreased in infants fed artificial standard milk formulae. However, the supplementation of formulae with these fatty acids in amounts close to that of human milk leads to tissue LC-PUFA patterns similar to those of breast-fed infants. However, the bioavailability of LC-PUFA depends on the typical LC-PUFA source; egg phospholipids increases both AA and DHA in plasma phospholipids and HDL more than a mixture of tuna and fungal triglycerides. Dietary LC-PUFA affects positively the growth and development of the infant and ameliorates the visual and cognitive functions, particularly in preterm infants. Likewise, LC-PUFA improves intestinal repair in severe protein-energy malnutrition; therefore, its qualitative and quantitative dietary supply should be considered.

Brain-specific lipids from marine, lacustrine, or terrestrial food resources: potential impact on early African Homo sapiens

Comparison of Triglycerides and Phospholipids as Supplemental Sources of Dietary Long-Chain Polyunsaturated Fatty Acids in Piglets

BackgroundThe functions, actions, and regulation of tissue metabolism affected by the consumption of long chain polyunsaturated fatty acids (LC-PUFA) from fish oil and other sources remain poorly understood; particularly how LC-PUFAs affect transcription of genes involved in regulating metabolism. In the present work, mice were fed diets containing fish oil rich in eicosapentaenoic acid and docosahexaenoic acid, fungal oil rich in arachidonic acid, or the combination of both. Liver and hippocampus tissue were then analyzed through a combined gene expression- and lipid- profiling strategy in order to annotate the molecular functions and targets of dietary LC-PUFA.ResultsUsing microarray technology, 329 and 356 dietary regulated transcripts were identified in the liver and hippocampus, respectively. All genes selected as differentially expressed were grouped by expression patterns through a combined k-means/hierarchical clustering approach, and annotated using gene ontology classifications. In the liver, groups of genes were linked to the transcription factors PPARα, HNFα, and SREBP-1; transcription factors known to control lipid metabolism. The pattern of differentially regulated genes, further supported with quantitative lipid profiling, suggested that the experimental diets increased hepatic β-oxidation and gluconeogenesis while decreasing fatty acid synthesis. Lastly, novel hippocampal gene changes were identified.ConclusionsExamining the broad transcriptional effects of LC-PUFAs confirmed previously identified PUFA-mediated gene expression changes and identified novel gene targets. Gene expression profiling displayed a complex and diverse gene pattern underlying the biological response to dietary LC-PUFAs. The results of the studied dietary changes highlighted broad-spectrum effects on the major eukaryotic lipid metabolism transcription factors. Further focused studies, stemming from such transcriptomic data, will need to dissect the transcription factor signaling pathways to fully explain how fish oils and arachidonic acid achieve their specific effects on health.