The apparent increased consumption of LA, which was primarily from soybean oil, has likely decreased tissue concentrations of EPA and DHA during the 20th century.

Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of ω-3-and ω-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy 1 . We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissionsCorrespondence should be addressed to L.E.H.S. (lois.smith@childrens.harvard.edu).. Supplementary information is available on the Nature Medicine website. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http:// www.nature.com/naturemedicine/. HHS Public AccessAuthor manuscript Nat Med. Author manuscript; available in PMC 2015 July 05. Published in final edited form as:Nat Med. 2007 July ; 13(7): 868-873. doi:10.1038/nm1591. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive ω-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of ω-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-α. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of ω-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in ω-3-PUFA, and premature infants lack the important transfer from the mother to the infant of ω-3-PUFA that normally occurs in the third trimester of pregnancy 2 . Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.Ocular neovascularization is the most common cause of blindness in all age groups: retinopathy of prematurity in children, diabetic retinopathy in working-age adults and agerelated macular degeneration in the elderly. In principle, destructive angiogenesis in the eye can be ameliorated by either direct inhibition of neovascularization or by controlling vessel loss in order to reduce the hypoxic stimulus that drives neovascularization. Retinopathy is modeled in the mouse eye with oxygen-induced vessel loss, which precipitates hypoxiainduced retinopathy, allowing for assessment of retinal vessel loss, vessel regrowth after injury and pathological angiogenesis 1 .The role of lipids in angiogenesis is just beginning to be defined 3,4 . The major polyunsaturated fatty acids (PUFA) found in the retina a...

Randomised controlled trials (RCT) of mixed n-6 and n-3 PUFA diets, and meta-analyses of their CHD outcomes, have been considered decisive evidence in specifically advising consumption of 'at least 5 -10 % of energy as n-6 PUFA'. Here we (1) performed an extensive literature search and extracted detailed dietary and outcome data enabling a critical examination of all RCT that increased PUFA and reported relevant CHD outcomes; (2) determined if dietary interventions increased n-6 PUFA with specificity, or increased both n-3 and n-6 PUFA (i.e. mixed n-3/n-6 PUFA diets); (3) compared mixed n-3/n-6 PUFA to n-6 specific PUFA diets on relevant CHD outcomes in meta-analyses; (4) evaluated the potential confounding role of trans-fatty acids (TFA). n-3 PUFA intakes were increased substantially in four of eight datasets, and the n-6 PUFA linoleic acid was raised with specificity in four datasets. n-3 and n-6 PUFA replaced a combination of TFA and SFA in all eight datasets. For non-fatal myocardial infarction (MI) þ CHD death, the pooled risk reduction for mixed n-3/n-6 PUFA diets was 22 % (risk ratio (RR) 0·78; 95 % CI 0·65, 0·93) compared to an increased risk of 13 % for n-6 specific PUFA diets (RR 1·13; 95 % CI 0·84, 1·53). Risk of non-fatal MI þ CHD death was significantly higher in n-6 specific PUFA diets compared to mixed n-3/n-6 PUFA diets (P¼ 0·02). RCT that substituted n-6 PUFA for TFA and SFA without simultaneously increasing n-3 PUFA produced an increase in risk of death that approached statistical significance (RR 1·16; 95 % CI 0·95, 1·42). Advice to specifically increase n-6 PUFA intake, based on mixed n-3/n-6 RCT data, is unlikely to provide the intended benefits, and may actually increase the risks of CHD and death.

Docosahexaenoic acid (DHA; 22:6n-3) is a critical constituent of the brain, but its metabolism has not been measured in the human brain in vivo. In monkeys, using positron emission tomography (PET), we first showed that intravenously injected [1-11 C]DHA mostly entered nonbrain organs, with ?0.5% entering the brain. Then, using PET and intravenous [1-11 C]DHA in 14 healthy adult humans, we quantitatively imaged regional rates of incorporation (K*) of DHA. We also imaged regional cerebral blood flow (rCBF) using PET and intravenous [15 O]water. Values of K* for DHA were higher in gray than white matter regions and correlated significantly with values of rCBF in 12 of 14 subjects despite evidence that rCBF does not directly influence K*. For the entire human brain, the net DHA incorporation rate J in , the product of K*, and the unesterified plasma DHA concentration equaled 3.8 6 1.7 mg/day. This net rate is equivalent to the net rate of DHA consumption by brain and, considering the reported amount of DHA in brain, indicates that the half-life of DHA in the human brain approximates 2.5 years. Thus, PET with [1-11 C]DHA can be used to quantify regional and global human brain DHA metabolism in relation to health and

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is highly concentrated in CNS tissues. Although breast milk contains the fatty acids DHA and arachidonic acid, infant formulas marketed in North America do not contain these nutrients. The potential deleterious effects of rearing infants with formulas devoid of these nutrients was assessed by comparing nurseryreared rhesus macaque infants (Macaca mulatta) fed standard formula with infants fed standard formula supplemented with physiologically relevant concentrations of DHA (1.0%) and arachidonic acid (1.0%). Neurobehavioral assessments were conducted on d 7, 14, 21, and 30 of life using blinded raters. The 30-min assessment consisted of 45 test items measuring orienting, temperament, reflex capabilities, and motor skills. Plasma concentrations of DHA in standard formula-fed infants were significantly lower than those fed supplemented formula or mother-raised (breast-fed) infants; however, infants fed the supplemented formula exhibited higher arachidonic acid levels than either mother-reared infants or infants fed standard formula. Infant monkeys fed the supplemented formula exhibited stronger orienting and motor skills than infants fed the standard formula, with the differences most pronounced during d 7 and 14. This pattern suggests an earlier maturation of specific visual and motor abilities in the supplemented infants. Supplementation did not affect measures of activity or state control, indicating no effect on temperament. These data support the assertion that preformed DHA and arachidonic acid in infant formulas are required for optimal development. There has been great interest in understanding the role of the long-chain fatty acids in promoting optimal cognitive and neurologic development. Although these nutrients are present in all mammalian breast milks, commercially available infant formulas do not support the tissue requirement for these nutrients in developing infants (1-4). The LC-PUFAs AA (20:4 n-6) and DHA (22:6 n-3) are selectively concentrated in the cellular membranes of neural and retinal tissues (5). Although human infants are able to synthesize AA and DHA from the precursor molecules linoleic acid (18:2 n-6) and ␣-linolenic acid (18:3 n-3) (6 -8), the rate of synthesis appears to be inadequate to meet the developmental demands of infants (7). In addition, uptake of DHA into brain tissue is more efficient than formation of DHA from ␣-linolenic acid (9). Human breast milk from women in all countries studied delivers both preformed AA and DHA to the developing infant (10). In contrast, commercially available infant formulas in the United States are virtually devoid of DHA and AA but contain the precursor fatty acids 18:2 n6 and 18:3 n3 (11). Thus, formulafed infants exhibit lower levels of AA and DHA in blood and brain tissues relative to their breast-fed counterparts [blood (12, 13); brain (1-4)]. These findings have prompted efforts to determine the physiologic benefits of LC-PUFA, particularly DHA, in infant nutrition and development....

The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.

Our previous work demonstrated that a decrease in brain docosahexaenoic acid (DHA) in rodents was associated with poorer performance in the Morris water maze. In this study we showed a deficit in spatial task performance of n‐3 deficient rats using the Barnes circular maze, which is similar to the Morris maze in that both tests require an escape response. Deficiency has been accomplished through the use of a two generational model in which the dam is deprived of n‐3 fatty acid sources and her offspring are then weaned to the same deficient diet. There was a loss of 56% of total brain DHA in n‐3 deficient (n‐3 Def) in comparison to n‐3 adequate (n‐3 Adq) rats. Both n‐3 Def (n=11) and n‐3 Adq (n=10) rats learned to locate the escape tunnel during the four days of training (2 trials a day), as indicated by a progressive reduction in escape latencies and errors rate. However, during the first two days, n‐3 Def rats did not perform as well as n‐3 Adq, but differences between groups did not reach the significance. To evaluate memory retention, rats were retested in the Barnes maze ten days after the last training trial. In the retention testing, n‐3 Adq rats did not differ from n‐3 Def in escape latencies (27.3+6.0 sec vs 24.9+7.2 sec)) and errors rate (4.55+1.2 vs 3.80+1.1). One week after memory retention testing, the escape tunnel was moved to a new position (opposite to the original), and rats were retrained in five consecutive trials to find the new location of the target (reversal learning). Def rats required more time to find the new position of the escape tunnel (p=0.003). This increase in the escape latencies was accompanied by a significantly higher number of errors. So, this study demonstrated a deficit in spatial task performance rats with low brain DHA in the two generational model. This project was funded by the Intramural Research Program of the NIAAA/NIH.

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