Dietary effects on brain fatty acid composition: the reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys.

Open AccessPublished:February 01, 1990DOI:
      This paper is only available as a PDF. To read, Please Download here.
      Rhesus monkeys given pre- and postnatal diets deficient in n-3 essential fatty acids develop low levels of docosahexaenoic acid (22:6 n-3, DHA) in the cerebral cortex and retina and impaired visual function. This highly polyunsaturated fatty acid is an important component of retinal photoreceptors and brain synaptic membranes. To study the turnover of polyunsaturated fatty acids in the brain and the reversibility of n-3 fatty acid deficiency, we fed five deficient juvenile rhesus monkeys a fish oil diet rich in DHA and other n-3 fatty acids for up to 129 weeks. The results of serial biopsy samples of the cerebral cortex indicated that the changes of brain fatty acid composition began as early as 1 week after fish oil feeding and stabilized at 12 weeks. The DHA content of the phosphatidylethanolamine of the frontal cortex increased progressively from 3.9 +/- 1.2 to 28.4 +/- 1.7 percent of total fatty acids. The n-6 fatty acid, 22:5, abnormally high in the cerebral cortex of n-3 deficient monkeys, decreased reciprocally from 16.2 +/- 3.1 to 1.6 +/- 0.4%. The half-life (t 1/2) of DHA in brain phosphatidylethanolamine was estimated to be 21 days. The fatty acids of other phospholipids in the brain (phosphatidylcholine, -serine, and -inositol) showed similar changes. The DHA content of plasma and erythrocyte phospholipids also increased greatly, with estimated half-lives of 29 and 21 days, respectively. We conclude that monkey cerebral cortex with an abnormal fatty acid composition produced by dietary n-3 fatty acid deficiency has a remarkable capacity to change its fatty acid content after dietary fish oil, both to increase 22:6 n-3 and to decrease 22:5 n-6 fatty acids. The biochemical evidence of n-3 fatty acid deficiency was completely corrected. These data imply a greater lability of the fatty acids of the phospholipids of the cerebral cortex than has been hitherto appreciated.


        • Connor W.E.
        • Neuringer M.
        • Lin D.
        The incorporation of docosahexaenoic acid into the brain of monkeys deficient in omega-3 essential fatty acids.
        Clin. Res. 1985; 33 (Abstract): 598
        • O'Brien J.S.
        Stability of the myelin membrane.
        Science. 1986; 147: 1099-1107
        • Crawford M.A.
        • Sinclair A.J.
        Nutritional influences in evolution of mammalian brain.
        Lipids, Malnutrition and the Developing Brain. Ciba Foundation Symposium. Associated Scientific Publishers, Amsterdam1972: 267-287
        • Crawford M.A.
        • Casperd N.M.
        • Sinclair A.J.
        The long-chain metabolites of linoleic and linolenic acids in liver and brain in herbivores and carnivores.
        Comp. Biochem. Physiol. 1976; 54B: 395-401
        • O'Brien J.S.
        • Fillerup D.L.
        • Mead J.F.
        Quantification and fatty acid and fatty aldehyde composition of etha-nolamine, choline, and serine glycerophosphatides in human cerebral gray and white matter.
        J. Lipid Res. 1964; 5: 329-338
        • Clandinin M.T.
        • Chappell J.E.
        • Leong S.
        • Heim T.
        • Swyer P.R.
        • Chance G.W.
        Intrauterine fatty acid accretion rates in human brain: implications for fatty acid requirements.
        Early Hum. Dev. 1980; 4: 121-129
        • Clandinin M.T.
        • Chappell J.E.
        • Leong S.
        • Heim T.
        • Swyer P.R.
        • Chance G.W.
        Extrauterine fatty acid accretion in infant brain: implications for fatty acid requirements.
        Early Hum. Dev. 1980; 4: 131-138
        • Neuringer M.
        • Connor W.E.
        • Van Patten C.
        • Barstad L.
        Dietary omega-3 fatty acid deficiency and visual loss in infant rhesus monkeys.
        J. Clin. Invest. 1984; 73: 272-276
        • Connor W.E.
        • Neuringer M.
        • Barstad L.
        • Lin D.S.
        Dietary deprivation of linolenic acid in rhesus monkeys: effects on plasma and tissue fatty acid composition and on visual function.
        Trans. Assoc. Am. Physicians. 1984; 97: 1-9
        • Neuringer M.
        • Connor W.E.
        • Lin D.S.
        • Barstad L.
        • Luck S.J.
        Biochemical and functional effects of prenatal and postnatal omega-3 fatty acid deficiency on retina and brain in rhesus monkeys.
        Proc. Natl. Acad. Sci. USA. 1986; 83: 40214025
        • Portman O.W.
        • Alexander M.
        • Maruffo C.A.
        Nutritional control of arterial lipid composition in squirrel monkeys: major ester classes and types of phospholipids.
        J. Nutr. 1967; 91: 35-46
        • Bligh E.G.
        • Dyer W.J.
        A rapid method of total lipid extraction and purification.
        Can. J. Biochem. Physiol. 1959; 37: 911-917
        • Rose H.G.
        • Oklander M.
        Improved procedure for the extraction of lipids from human erythrocytes.
        J. Lipid Res. 1965; 6: 428-431
        • Folch J.
        • Lees M.
        • Sloane Stanley G.H.
        A simple method for the isolation and purification of total lipids from animal tissues.
        J. Biol. Chem. 1957; 226: 497-509
        • Miljanich G.P.
        • Sklar L.A.
        • White D.L.
        • Dratz E.A.
        Desaturated and dipolyunsaturated phospholipid in bovine retinal rod outer segment disk membrane.
        Biochim. Biophys. Acta. 1979; 552: 94-306
        • Connor W.E.
        • Lin D.S.
        Placental transfer of cholesterol^-1^ into rabbit and guinea pig fetus.
        J. Lipid Res. 1967; 8: 558-564
        • Vitiello F.
        • Zanetta J.P.
        Thin-layer chromatography of phospholipids.
        J. Chromatogr. 1978; 166: 637-640
        • Morrison W.R.
        • Smith L.M.
        Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol.
        J. Lipid Res. 1964; 5: 600-608
        • Rapp J.H.
        • Connor W.E.
        • Lin D.S.
        • Inahara T.
        • Porter J.M.
        Lipids of human atherosclerotic plaques and xanthomas: clues to the mechanism of plaque progression.
        J. Lipid Res. 1983; 24: 1329-1335
        • Shipley R.A.
        • Clark R.E.
        Tracer Method for in vivo Kinetic—Theory and Application. Academic Press, New York1972: 145-162
        • Trapp B.D.
        • Bernson J.
        Changes in phosphoglyc-eride fatty acids of rat brain induced by linoleic and linolenic acids after pre- and postnatal fat deprivation.
        J. Neurochem. 1977; 28: 1009-1013
        • Snedecor G.W.
        • Cochran W.G.
        Statistical Methods. Iowa State University Press, Ames, IA1967: 91-95
        • Dawson R.M.C.
        • Richter D.
        The phosphorus metabolism of the brain.
        Proc. R. Soc. 1950; B137: 252-267
        • Ansell G.B.
        • Dohmen H.
        The metabolism of individual phospholipids in rat brain during hypoglycaemia, anaesthesia and convulsions.
        J. Neurochem. 1957; 2: 1-10
        • Corkin D.R.
        • Sun G.Y.
        Characterization of the enzymic transfer of arachidonyl groups to 1-acyl-phosphoglyc-erides in mouse synaptosome fraction.
        J. Neurochem. 1978; 30: 77-82
        • Fisher S.K.
        • Rowe C.E.
        The acylation of lysophosphatidylcholine by subcellar fractions of guinea pig cerebral cortex.
        Biochim. Biophys. Acta. 1980; 618: 231-241
        • Anderson G.
        • Connor W.E.
        Uptake of fatty acids by developing rat brain.
        Lipids. 1988; 23: 286-290
        • Pitkin R.M.
        • Connor W.E.
        • Lin D.S.
        Cholesterol metabolism and placental transfer in pregnant rhesus monkey.
        J. Clin. Invest. 1972; 15: 2582-2592
        • Oldendorf W.H.
        Permeability of the blood-brain barrier.
        in: Tower D.B. The Nervous System. Raven Press, New York1975: 279-289
        • Odutuga A.A.
        Reversal of brain essential fatty acid deficiency in the rat by dietary linoleate, linolenate and arachi-donate.
        Int. J. Biochem. 1981; 13: 1035-1038
        • Walker B.L.
        Maternal diet and brain fatty acids in young rats.
        Lipids. 1967; 2: 497-500
        • Sanders T.A.B.
        • Mistry M.
        • Naismith D.J.
        The influence of a maternal diet rich in linoleic acid on brain and retinal docosahexaenoic acid in the rat.
        Br. J. Nutr. 1984; 51: 57-66
        • Youyou A.
        • Durand G.
        • Pascal G.
        • Piccotti M.
        • Dumont O.
        • Bourre J.M.
        Recovery of altered fatty acid composition induced by a diet devoid of n-3 fatty acids in myelin, synaptosomes, mitochondria and microsomes of developing rat brain.
        J. Neurochem. 1986; 46: 224-227
        • Homomayoun P.
        • Durand G.
        • Pascal G.
        • Bourre J.M.
        Alteration in fatty acid composition of adult rat brain capillaries and choroid plexus induced by a diet deficient in n-3 fatty acids: slow recovery after substitution with a nondeficient diet.
        J. Neurochem. 1988; 51: 45-48
        • Leyton J.
        • Dairy P.J.
        • Crawford M.A.
        Differential oxidation of saturated and unsaturated fatty acids in vivo in the rat.
        Br. J. Nutr. 1987; 57: 383-393
        • Anderson G.J.
        • Connor W.E.
        • Corliss J.D.
        Docosahexaenoic acid is the preferred dietary n-3 fatty acid for the development of the brain and retina.
        Pediatr. Res. 1989; (In press)
        • Cocchi M.
        • Pignatti C.
        • Carpigiani M.
        • Tarozzi G.
        • Turchetto E.
        Effect of C 18:3 (n-3) dietary supplementation on the fatty acid composition of the rat brain.
        Acta Vitami-nol. Enzymol. 1984; 6: 151-156
        • Tarozzi G.
        • Barzanti V.
        • Biagi P.L.
        • Cocchi M.
        • Lodi R.
        • Maranesi M.
        • Pignatti C.
        • Turchetto E.
        Fatty acid composition of single brain structures following different al-pha-linolenate dietary supplementations.
        Acta Vitaminol. Enzymol. 1984; 6: 157-163
        • Carlson S.E.
        • Carver J.D.
        • House S.G.
        High fat diets varying in ratios of polyunsaturated fatty acid and lino-leic to linolenic acid: a comparison of rat neural and red cell membrane phospholipids.
        J. Nutr. 1986; 11: 718-725
        • Philbrick D.J.
        • Mahadevappa V.G.
        • Ackman R.G.
        • Holub B.J.
        Ingestion of fish oil or a derived n-3 fatty acid concentrate containing eicosapentaenoic acid affects fatty acid compositions of individual phospholipids of rat brain, sciatic nerve, and retina.
        J. Nutr. 1987; 17: 1663-1670
        • Hargreaves K.M.
        • Clandinin M.T.
        Dietary control of diacylphosphatidylethanolamine species in brain.
        Bio-chim. Biopkys. Acta. 1988; 962: 98-104
        • Op den Kamp J.A.F.
        • Roelofsen B.
        • Van Deenan L.L.M.
        Structural and dynamic aspects of phosphatidyl choline in human erythrocyte membrane.
        Trends Biochem. Sci. 1985; 10: 320-323
        • Connor W.E.
        • Neuringer M.
        The effects of n-3 fatty acid deficiency and repletion upon the fatty acid composition and function of the brain and retina.
        in: Karnovsky M.L. Leaf A. Bolis L.C. Biological Membranes: Abberrations in Membrane Structure and Function. Alan R. Liss, Inc., New York1988: 275-294
        • Lin D.S.
        • Connor W.E.
        • Anderson G.J.
        • Neuringer M.
        The effect of diet upon the phospholipid molecular species composition of monkey brain.
        FASEB J. 1989; 3 (abstract).: A945
        • Neuringer M.
        • Anderson G.J.
        • Connor W.E.
        The essentiality of n-3 fatty acids for development and function of retina and brain.
        Annu. Rev. Nutr. 1988; 8: 517-541
        • Neuringer M.
        • Connor W.E.
        Omega-3 fatty acids in brain and retina: evidence for their essentiality.
        Nutr. Rev. 1986; 44: 285-294