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Nutrition and Food Safety Laboratory Unit, Neurobiology of Lipids, Institut National de la Recherche Agronomique (INRA), Jouy-en-Josas, 78352 Cedex, France and * INSERM U26, Unité de Neuro-Pharmaco-Nutrition, Hôpital Fernand Widal, Paris, France
3To whom correspondence should be addressed. E-mail: fabien.pifferi{at}jouy.inra.fr.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • astrocytes • microvessels • endothelial cells • glucose transporters • (n-3) fatty acids
Numerous studies have shown that dietary PUFAs influence brain functions and neuronal activity [reviewed in (1)]. The brain membrane phospholipids of most species, including primates, have high concentrations of long-chain PUFAs such as docosahexaenoic acid [DHA,4 22:6(n-3)] and arachidonic acid [AA, 20:4(n-6)] (2). The specific accretion of DHA during perinatal development is considered to be essential for the proper functioning of the mammalian central nervous system (CNS) (3). Studies on rodents, nonhuman primates, and on newborn infants showed that a decreased DHA content of brain membrane phospholipids, induced by a diet low in (n-3) PUFA, results in abnormal learning ability, memory performance, and maturation of visual acuity (4–6). Changes in cognitive performance have been linked to the function of DHA in brain membranes because it modulates ion channels, synaptic signaling (1,7), and the storage and release of neurotransmitters (8–10). These effects are probably due to changes in membrane structure and dynamics (phospholipid composition and lipid raft formation), synaptic signaling involving eicosanoids, and the regulation of gene expression in the brain by nuclear factors (1,3,11).
Neuronal activity is tightly coupled to glucose utilization in associated brain areas and thus with the increased transfer of glucose from the blood to neurons (12). Glucose is distributed from the blood to the brain cells via specific membrane glucose transporters, mainly GLUT1 and GLUT3. It is first transported across the endothelial cells of the blood-brain barrier (BBB) by the 55-kDa GLUT1 and then into astrocytes by the 45-kDa GLUT1 isoform and into neurons by GLUT3 [reviewed in (13)]. Both the amounts of GLUT1 and the asymmetrical distribution of GLUT1 in the luminal (blood side), abluminal (brain side) and intracellular membranes, determine the basal and topical changes in glucose transport activity when neurons are activated (14–16). This activation increases brain glucose utilization, with parallel increases in GLUT1 protein and mRNA in the BBB and astrocytes (17). In contrast, GLUT3 is not considered to be a limiting step in neuron activation (16). Other adaptive changes in this increased glucose utilization are increased local cerebral blood flow and capillary density (18).
The altered neuronal activity in (n-3) fatty acid (FA)-deficient animals could result from changes in brain energy metabolism. The activity of membrane-bound Na+-K+-ATPase isoenzymes in the brain, which control energy consumption during neuronal activity, has been linked to the dietary intake of (n-3) FAs (from deficiency to high DHA intake) (4,19). We reported recently that the cerebral cortex and hippocampus of (n-3) FA-deficient rats have below normal rates of glucose utilization and oxidative phosphorylation (20). We postulated that the GLUT1 protein in deficient rats was functionally abnormal because its immunoreactivity was low. However, immunocytochemical staining of GLUT1 is not suitable for detecting a specific effect of dietary (n-3) FAs on the 2 GLUT1 isoforms because they are colocalized around blood vessels (20). Therefore, in this study, we determined the effect of an (n-3) FA-deficient diet on GLUT1 and GLUT3 glucose transporter expression (protein, mRNA) in the rat cerebral cortex.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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As previously described (20), only the first generation of adult male rats deficient in (n-3) FAs were used in this study. For that purpose, female Wistar rats (n = 20) fed a standard diet were assigned to 1 of 2 experimental groups 2 wk before mating; one group was fed a control diet supplying adequate contents of (n-6) and (n-3) PUFAs, whereas the other was fed a diet containing only (n-6) PUFAs [(n-3) deficient diet] (Table 1). The male pups were fed the same diet as their mothers [control or (n-3) deficient] from weaning until they were killed (3 mo). All rats were killed at the beginning of the light phase (0930–1000 h) to avoid any change in glucose metabolism due to diurnal variations in cerebral metabolic activity (21).
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Lipid analysis. Total lipids were extracted from cerebral cortex homogenates and microvessels (9). Phosphatidylcholine (PC), ethanolamine phosphoglycerolipids (EPGs), and phosphatidylserine (PS) were separated from total lipids by solid-phase extraction on a 500-mg aminopropyl-bonded silica column (BAKERBOND speTM Amino; Mallincroft Baker) (23). All eluents were dried under nitrogen, and the phospholipid fractions were transmethylated with 10% boron trifluoride (Fluka, Sokolab) at 90°C for 20 min (24). FAME were analyzed by GC (25); the FA composition is expressed as a weight percentage.
Assay of 45- and 55-kDa GLUT1 and GLUT3 by Western blotting. Samples of cerebral cortex homogenates and microvessels were sonicated and their protein contents were determined (10). They were then diluted in Tris-HCl buffer containing 20 mmol/L SDS, 4 mmol/L dithiothreitol, and a protease inhibitor cocktail (Roche Diagnostics). Proteins (30 µg for the homogenate and 5 µg for microvessels) were separated by SDS-PAGE and electrotransferred to a polyvinylidene fluoride (PVDF) membrane (Bio-Rad, 2 h at 40 mA). Membranes were incubated with Tris-base buffer containing 0.1% Tween 20 (v:v) and 5% milk (wt:v) for 8 h at 4°C, rinsed in Tris-buffered saline containing 0.05% (v:v) Tween 20 (TBST), and incubated with a rabbit anti-GLUT1 polyclonal IgG (Biogenesis, diluted 1:500 in TBST) at 4°C overnight. This antibody was raised against the COOH terminus of rat GLUT1, which is common to both the 45-kDa and 55-kDa isoforms. The membranes were washed several times in TBST and incubated with peroxidase-labeled anti-rabbit secondary antibody (Jackson Immunoresearch Laboratories) (diluted 1:20000) for 3 h at room temperature, and immunopositive areas were detected by enhanced chemiluminescence (Fujifilm LAS-1000 Plus Camera System, Fujifilm). Staining intensity was measured with Advanced Image Data Analyser software v. 3.22 (Raytest).
The PVDF membranes used to analyze the samples of the cerebral cortex homogenate were then stripped of GLUT1 antibody by immersion for 5 min in 0.2 mol/L NaOH, washed 3 times in TBST, and incubated in TBST + 5% milk (wt:v) for 8 h at 4°C. GLUT3 was immunodetected with an antibody to the COOH terminus of GLUT3 (goat anti-GLUT3 polyclonal IgG, diluted 1:100, Santa Cruz Biotechnology) using the experimental protocol described for GLUT1.
The densitometry for the 3 isoforms of GLUT was normalized with reference to ß-actin blotted on each membrane after stripping the antibodies with 0.2 mol/L NaOH. ß-Actin was assayed with a monoclonal mouse anti-ß-actin antibody (mouse ß-actin AC-74 monoclonal IgG, diluted 1:5000, Sigma), a labeled anti-mouse secondary antibody using the same procedure as for GLUT1 and GLUT3.
Assay of GLUT1 and GLUT3 mRNA by real-time quantitative RT-PCR. RNA extraction and cDNA synthesis. Total RNA was extracted from 3 cerebral cortex homogenates using the RNeasy midi lipid tissue kit (Quiagen). Cerebral cortex microvessel mRNA was prepared by lysing the basal lamina with proteinase K, followed by extraction with an RNeasy Midi Fibrous Tissue Kit, according to the manufacturer’s instructions (Quiagen). Total RNA was determined by measuring absorbance at 260 nm in a Biophotometer (Ependorf SARL). Total RNA (4 µg) was then reverse transcribed using the High Capacity cDNA Archive Kit (Applied Biosystems) according to the manufacturer’s instructions.
Real-time quantitative RT-PCR amplification. The 18S rRNA was used as the housekeeping gene to normalize the target gene values. The mRNA encoding GLUT1, GLUT3, and 18S rRNA was retrotranscribed into cDNA, and the cDNA was amplified by real-time quantitative RT-PCR using specific primers and probes optimized at 100% by the manufacturer (Assays-on-Demand, gene expression products, Applied Biosystems). The cDNA was quantified, using a Sequence Detector, from the cycle number (Ct) for threshold signal detection. PCR was performed using the ABI Prism 7000 Sequence Detection Systems (Applied Biosystems). GLUT1, GLUT3 mRNA, and 18S rRNA were amplified in a 25-µL reaction volume with 10 µL 2X TaqMan Universal Master Mix (Applied Biosystems), plus 1 µL 20X Assays-on-Demand (Rn00593670_m1 for GLUT1, Rn00567331_m1 for GLUT3 and Hs99999901_s1 for 18S rRNA). The thermal cycling conditions were as follows: initial denaturation at 95°C for 10 min plus 45 cycles at 95°C for 15 s and at 60°C for 1 min. The experiments were performed in triplicate for each data point. The amounts of GLUT1 and GLUT3 mRNA from each sample were normalized to that of 18S rRNA.
Statistical analyses. The results are expressed as means ± SEM (n = 6 independent determinations per diet group, except for RT-PCR where n = 3 determinations). Statistical comparisons between tissues (microvessels vs. homogenate) and between diet groups were performed by paired t test and unpaired t test, respectively. Statistical analyses were performed using STATVIEW software (Abacus Concepts). Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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4.5% of the total FAs in the PS fractions of microvessels and cortex, but the PS DHA content was 84% lower in the microvessels than in the cortex. Thus, the AA:DHA ratios in the 3 phospholipid classes were opposite in the microvessels and the cortex.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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We found that the FA composition of the microvessel membranes differed from that of the whole cortex, having a high AA content and a low DHA content. The AA:DHA ratio was 3- to 10-fold higher in the 3 phospholipid classes in microvessels than in those of the cerebral cortex; this was consistent with the results of Selivonchick et al. (26), supporting the role of endothelial cells in the synthesis of PUFA and in the specific delivery of DHA to brain membrane phospholipids (27). In vitro studies in cultured endothelial cells showed that newly synthesized AA was preferentially incorporated into membrane phospholipids, and DHA was preferentially secreted into the medium (27,28). The accumulation of AA in the endothelial cell membranes of peripheral vascular tissues could be linked to the local synthesis of eicosanoid mediators from the series 2 and 4, which are potent regulators of vascular physiology (29). Our data also show that the brain endothelial cells contain relatively high concentrations of other 20-C PUFAs [mainly 20:3(n-6) and 20:5(n-3)], which are potential precursors of the series 1, 3, and 5 eicosanoids that are implicated in vasoconstriction and vasodilation.
Despite the different FA profiles of the microvessels and cerebral cortex, (n-3) PUFA deficiency had similar effects on both tissues. The DHA content of the membrane phospholipids was decreased by 50%, and this decrease was specifically offset by an increase in (n-6) DPA (20). However, the cortex phospholipid membranes retained a comparatively high DHA content compared with the endothelial cells, reflecting the "avidity" of the brain for DHA, which may be due in part to a drastic deficiency-induced reduction in the metabolic loss of DHA from the brain membranes (30,31). The decreased DHA content of the microvessels was not accompanied by any change in AA, suggesting that the AA content is strongly regulated in the endothelial cells, possibly linked to its role as an eicosanoid mediator in these cells (29). In contrast, the AA content was not maintained in the cortex phospholipids of deficient rats, specifically in PC, in which it dropped by 50% as previously reported (20). This drop was specific to the cerebral cortex because no such modification was noted in other brain areas in the first generation of (n-3)-deficient rats (hippocampus and suprachiasmatic nucleus) (20).
The DHA content of the CNS membranes regulates several membrane transporters, receptors, G-protein signaling and enzymes [reviewed in (1,3,11)]. PUFAs and DHA may also modulate the function of glucose transporters, as suggested by the reduced use of 2-deoxyglucose (2-DG) by (n-3) PUFA-deficient brains (20). Several in vivo and in vitro studies demonstrated that PUFAs can activate the basal glucose uptake of the cells of peripheral tissues by modulating GLUT1 activity, by changes in membrane fluidity, and by activating the genes encoding the peroxisome proliferator-activated receptor 
(PPAR)-dependent pathways (32). Only 1 study on primary cultures of CNS astrocytes investigated the effect of PUFA on the regulation of glucose uptake (33). Cells in medium supplemented with AA had a greater 2-DG uptake than cells in medium supplemented with the saturated palmitic and arachidic FAs. The effect was rapid (20 min), and it was not blocked by cyclooxygenase or lipoxygenase inhibitors, indicating that AA acted directly on GLUT1 without the production of prostaglandins or leukotrienes.
Our data clearly indicate that (n-3) PUFA deficiency specifically decreased the GLUT1 protein content of endothelial cells (55-kDa isoform) and astrocytes (45-kDa isoform) by 25–30%, and did not change neuronal GLUT3 protein content. This decrease was consistent with the lower GLUT1 immunoreactivity determined by immunohistochemistry and the 30% lower glucose utilization previously measured in the cerebral cortex of (n-3) PUFA-deficient rats (20). Our real-time quantitative RT-PCR data showed no change in the amount of GLUT1 mRNA, indicating that low GLUT1 protein concentration in (n-3) PUFA-deficient microvessels and astrocytes could be due to post-transcriptional events. Although GLUT1 expression can be regulated at the transcriptional level (17), it seems that post-transcriptional events are principally involved in GLUT1 regulation via changes in translation and stabilization of the GLUT1 transcript mRNA (34,35). We hypothesized that (n-3) fatty acid deficiency could affect the stability events probably via the modulation of transcription factor PPAR because its agonists increased glucose metabolism in endothelial cells and astrocytes by increasing the stability of GLUT1 mRNA without any change in GLUT1 mRNA level (36).
The low glucose utilization in the brains of (n-3) PUFA-deficient animals is thus related to specific changes in the amounts of the 2 main glucose transporter proteins: BBB GLUT1 regulating glucose entry into the brain, and astrocytic GLUT1 regulating glucose metabolism in lactate, which is also used as an energetic substrate by glutamatergic neurons during learning and memory processing (17). This decreased glucose utilization could be due to a specific decrease in DHA and/or a change in the ratio of AA to DHA in membrane phospholipids. The molecular mechanisms now have to be identified, notably at the post-transcriptional level of GLUT1 expression. Changes in GLUT1 conformation and activity must also be considered in the light of the data on the specific effects of (n-3) PUFA on activities of nerve membrane proteins (rhodopsin, Na+-K+-ATPase) (37,38). Moreover, it is possible that (n-3) PUFA have indirect effects on GLUT1 by reducing the activity and/or gene expression of other proteins involved in energy metabolism in the brain (39), resulting in reduced GLUT1 protein synthesis. Animals that lack (n-3) PUFA have decreased glucose utilization and also oxidative phosphorylation, together with below-normal cytochrome oxidase activity (20). Last, microarray analyses showed that dietary PUFA modulate the expression of genes involved in energy metabolism, such as those encoding ATP synthase, cytochrome c oxidase and NADH dehydrogenase (39). Further studies in vivo and of an in vitro model of BBB endothelial cells cultured together with astrocytes (40) and of astrocytes cultured alone are now required for investigation of the specific effects of (n-3) and (n-6) PUFAs, particularly DHA and AA, on glucose utilization and GLUT1 regulation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by grants from the French Ministère de l’Éducation Nationale de la Recherche et de la Technologie, the Institut National de la Recherche Agronomique (INRA), and the Groupe Lipides Nutrition (GLN).
4 Abbreviations used: AA, arachidonic acid; BBB, blood-brain barrier; CNS, central nervous system; 2-DG, 2-deoxyglucose; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EPG, ethanolamine phosphoglycerolipid; FA, fatty acid; GLUT, glucose transporter; PC, phosphatidylcholine; PPAR, peroxisome proliferator-activated receptor ; PS, phosphatidylserine; PVDF, polyvinylidene fluoride.
Manuscript received 21 March 2005. Initial review completed 12 April 2005. Revision accepted 10 June 2005.
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