Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer’s disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease.

Docosahexaenoic acid (DHA) (22:6) is a polyunsaturated fatty acid of the n - 3 series which is believed to be a molecular target for lipid peroxides (LPO) formation. Its ubiquitous nature in the nervous tissue renders it particularly vulnerable to oxidative stress, which is high in brain during normal activity because of high oxygen consumption and generation of reactive oxygen species (ROS). Under steady state conditions potentially harmful ROS and LPO are maintained at low levels due to a strong antioxidant defense mechanism, which involves several enzymes and low molecular weight reducing compounds. The present review emphasizes a paradox: a discrepancy between the expected high oxidability of the DHA molecule due to its high degree of unsaturation and certain experimental results which would indicate no change or even decreased lipid peroxidation when brain tissue is supplied or enriched with DHA. The following is a critical review of the experimental data relating DHA levels in the brain to lipid peroxidation and oxidative damage there. A neuroprotective role for DHA, possibly in association with the vinyl ether (VE) linkage of plasmalogens (pPLs) in combating free radicals is proposed.

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Lipid profile results are too often neglected by the clinician despite increasing knowledge in the modifications related to septic state as well as the importance of these values in the prognosis of the critically ill. Lipid administration (enterally or parenterally) should be guided by better knowledge of the lipid metabolism of the patient.

BBS4 is one of several proteins whose defects cause Bardet-Biedl syndrome (BBS), a multi-systemic disorder, manifesting with marked obesity. BBS4 polymorphisms have been associated with common non-syndromic morbid obesity. BBS4 obesity molecular mechanisms, and the role of the BBS4 gene in adipocyte differentiation and function are not entirely known. We now show that Bbs4 plays a direct and essential role in proliferation and adipogenesis: silencing of Bbs4 in 3T3F442A preadipocytes induced accelerated cell division and aberrant differentiation, evident through morphologic studies (light, scanning and transmission electron microscopy), metabolic analyses (fat accumulation, fatty acid profile and lipolysis) and adipogenic markers transcripts (Cebpα, Pparγ, aP2, ADRP, Perilipin). Throughout adipogenesis and when challenged with fat load, Bbs4 silenced cells accumulate significantly more triglycerides than control adipocytes, albeit in smaller (yet greater in number) droplets containing modified fatty acid profiles. Thus, greater fat accumulation in the silenced cells is a consequence of both a higher rate of adipocyte proliferation and of aberrant differentiation leading to augmented aberrant accumulation of fat per cell. Our findings suggest that the BBS obesity might be partly due to a direct role of BBS4 in physiological and pathophysiological mechanisms that underlie adipose tissue formation relevant to obesity.

The fatty acid (FA) composition and distribution in a variety of phospholipids (PL) and neutral lipids (NL) at two discrete stages during the embryonic rat brain development were investigated. Over 96% of the FA were acylated into fetal brain PL at embryonic day 17 after the peak of neuronal proliferation and at embryonic day 20, one day prior to delivery. Phosphatidylcholine constituted approximately 60% of the total PL pool, phosphatidylethanolamine (PE) 30%, phosphatidylserine (PS) 6%, and phosphatidylinositol (PI) 4%. The diacylglycerols and triacylglycerols constituted 1-2% of the fetal brain lipids. alpha-Linolenic acid (18:3n-3) and linoleic acid (18:2n-6) were found in very low amounts in all fetal brain PL and NL. The percentage of the n-6 polyunsaturated FA, consisting of arachidonic acid (AA), 22:4n-6 and 22:5n-6, remained unchanged in all the fractions, except in PI, in which the proportion of AA increased. The concentration of docosahexaenoic acid (DHA) increased with age in all the fractions, with the bulk of accumulation accounted for by its increase in PE and, to a lesser extent, in PS. This finding suggests a "DHA accretion spurt" during the last three days of pregnancy.

Studies were conducted on the prenatal rat produce major disturbances in cell function, including given a single intraamniotic injection of ethyl docosahex-DNA fragmentation, damage to membrane ion transaenoate (Et-DHA; 9.6-12 mmol per fetus) or subjected porters and other proteins with rises in intracellular to an n-3 fatty acid-deficient diet to assess the role of Ca 2concentrations, and peroxidation of lipids (Hallidocosahexaenoate on oxidative stress during episodes well and Chirico, 1993). Evidence has accumulated to of ischemia. A time-dependent decrease in the ability of brain slices from animals treated with Et-DHA to produce suggest a causal relationship between oxidative stress thiobarbituric acid-reactive substance (TBARS), most and neurodegenerative disorders (Coyle and Puttfarpronounced after 1 day (from 58.1 ± 4.22 to 15.9 ± 1.6 cken, 1993). Brain trauma is linked to generation of nmol/mg of DNA), was noticed on stimulation with Fe2~.reactive oxygen species and production of lipid peroxBrain slices from fetuses treated for 1 day with Et-DHA ides (LPOs); furthermore, there are indications that and those from untreated fetuses produced TBARS levels oxygen radical formation and LPO are involved in of 46.7 ± 6.5 and 114.8 ± 10.8 nmol/mg of DNA, respecpathophysiological processes such as hypoperfusion, tively, after a 20-mm occlusion of the fetal-maternal ciredema, and axonal conduction failure (Hall and Braughculation at embryonic day 20, suggesting a protective ler, 1989). At the biochemical level, reactive oxygen effect of Et-DHA. The protective effeôt of a single dose species appear to alter NMDA receptor (Goel et al., of Et-DHA in utero remained high upto 3 days after injec-1993) and synaptosomal membrane (Viani et al., tion (p < 0.001) and was long-lasting, yet not significant, up to 3 days following birth. In agreement with a reduction 1995) functions, whereas oxygen radical scavengers in TBARS production by slices, the endogenous levels of can block posttraumatic consequences and promote TBARS in brains of Et-DHA-treated animals were lower functional recovery and survival in experimental anithan in the controls. Et-DHA-injected fetuses exhibited mals (Hall and Braughler, 1993). significantly higher levels of esterified DHA than the nonBrain tissue is particularly vulnerable to oxidative injected controls. n-3-deficient diet given to dams for 2 damage for several reasons, as recently discussed (Halweeks before birth did not affect the levels of TBARS liwell, 1992). Of these, the high content of polyunsatuproduction in control fetal brain slices but abolished the rated fatty acids (PUFAs), which are especially sensiincrease caused by ischemia. Et-DHA administration for tive to free radical attack, deserves attention. Being a 24 h to n-3-deficient fetuses reduced the amount of IBARS produced by the fetal brain slices from 49.1 major PUFA, docosahexaenoate (DHA) has the poten-± 8.5 to 31.7 ± 4.1 nmol/mg of DNA. A protective effect tial to increase the susceptibility of the membranes to fro...

Cell replacement therapy is being investigated for the treatment of neurodegenerative disorders. Adult autologous bone marrow-derived mesenchymal stem cells (MSCs) have been induced to differentiate into neuron-like cells harboring a variety of neuronal markers and transcription factors. Neural tissue characteristically contains high proportions of docosahexaenoic acid (DHA) and arachidonic acid (AA). In this study, evaluation of the fatty acid profile of differentiated neuron-like cells revealed a very low level of DHA, similar to that in MSCs but different from typical neurons. Supplementation of the medium with DHA alone resulted in increased levels of DHA but concomitant low levels of AA. However, supplementation with both DHA and AA yielded a fatty acid profile resembling that of neural tissue. It also resulted in enhanced outgrowth of neurite-like processes, hallmarks of neuronal differentiation. These findings demonstrate the essentiality of DHA and AA supplementation in the process of induced neuronal differentiation and have important implications for the development of cell replacement strategies of neural repair.-Kan, I., E. Melamed, D. Offen, and P. Green. Docosahexaenoic acid and arachidonic acid are fundamental supplements for the induction of neuronal differentiation. J. Lipid Res. 2007. 48: 513-517.