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-Linolenic Acid Deficient Diet in Formula-fed Piglets1
Department of Paediatrics, University of British Columbia, Vancouver, Canada V5Z 4H4
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • essential fatty acids • docosahexaenoic acid • arachidonic acid • dopaminergic • serotoninergic • piglets
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Arachidonic acid
[20:4(n-6)] and 22:6(n-3) are derived from the dietary essential
fatty acid (EFA) linoleic acid [18:2(n-6)] and 
-linolenic acid
[18:3(n- 3)], respectively, by sequential desaturation and
elongation (Sprecher et al. 1995
), and by dietary
intake. Brain phospholipids contain high proportions of 20:4(n-6) and
22:6(n-3), but only small amounts of the precursors 18:2(n-6) and
18: 3(n-3) (Sastry 1985
). Dietary deficiency of
(n-6) and (n-3) fatty acids results in reduced 20:4(n-6) and 22:6(n-3),
respectively, in the brain and influences various aspects of neural
function at the behavioral level, including changes on behavioral tests
of learning, memory and habituation (Bourre et al. 1989
,
Enslen et al. 1991
, Frances et al. 1996
,
Lamptey and Walker 1976
, Wainwright and Ward 1997
, Yamamoto et al. 1988
). The biochemical
explanation for the effects of dietary (n-6) and (n-3) fatty acids on
brain functions are not known, although changes in some central nervous
system (CNS) enzyme activities (Bourre et al. 1989
) and
in the levels of monoaminergic neurotransmitters (Delion et al. 1994
and 1996
) were reported in rats after prolonged feeding
with (n-3) fatty acid-deficient diets. Changes in monoamine
metabolism are of interest because the dopaminergic and serotoninergic
systems are involved in the regulation of some behaviors, memory and
learning processes (Brozosky et al. 1979
, McEntee and Cook 1991
, Simon et al. 1980
). Previous
studies concerning the effects of dietary (n-6) and (n-3) fatty acid
deficiency on behavior and brain fatty acids used animals fed deficient
diets through gestation and early development, and often for one or
more generations (Bourre et al. 1989
, Enslen et al. 1991
, Frances et al. 1996
, Lamptey and Walker 1976
, Reisbick et al. 1990
,
Wainwright and Ward 1997
, Yamamoto et al. 1988
).
Despite substantial evidence of the importance of 20:4(n-6) and
22:6(n-3) in normal brain function, little is known about the pathways
by which the brain normally acquires (n-6) and (n-3) fatty acids.
Recent studies, however, have identified fatty acid-binding and
-transport proteins in the developing brain (Utsunomiya et al. 1997
, Xu et al. 1996
). The brain takes up
18:2(n-6) and 18:3(n-3), and recent studies have shown the brain is
able to synthesize 20:4(n-6) and 22:6(n-3) from the 18 carbon chain
precursors (Dhopeshwarkar et al. 1971a
and 1971b
;
Edmond et al. 1998
, Moore et al. 1990
and 1991
). However, the importance of uptake of 20:4(n-6) and
22:6(n-3) from plasma rather than desaturation-elongation of
18:2(n-6) and 18:3(n-3) as a source of 20:4(n-6) and 22:6(n-3) for the
growing brain is not yet clear. Numerous studies showed that blood
lipid levels of 20:4(n-6), 22:6(n-3) and 22:6(n-3) are lower in infants
fed formula with 18:2(n-6) and 18:3(n-3), but not 20:4(n-6), than are
those in breast fed infants (Innis et al. 1994b
, Makrides et al. 1995
,
Putnam et al. 1982
). Thus, it is important to understand
the relative importance of dietary 18:2(n-6) and 18:3(n-3), compared to
20:4(n-6) and 22:6(n-3), on the composition of brain fatty acids
and neurotransmitter metabolism. The purpose of this study was to
determine the importance of dietary 18:2(n-6) and 18:3(n-3), and their
longer-chain derivatives 20:4(n-6) and 22:6(n-3), respectively, on
frontal cortex levels of dopaminergic and serotoninergic
neurotransmitters in neonatal piglets. Piglets were used for these
studies because the perinatal patterns of piglet brain growth and pig
milk lipids resemble those of humans and because pigs can be
bottle-fed from birth (Innis 1992
). The latter
allows complete control of the diet fatty acid composition in the early
neonatal period.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Newborn male piglets weighing >1 kg at birth and <12 h old (Kintail
Meats, Langley, British Columbia) were assigned to be fed one of four
formula diets (n = 6/group). The composition of the
liquid formulas was based on the macro- and micro-nutrient
composition of pig milk and differed only in the composition of the
fat. Two of the formulas were deficient (D) in 18:2(n-6) and 18:3(n-3),
with about 0.8% energy 18:2(n-6) and 0.05% energy 18:3(n-3)
[18:2(n-6)+18:3(n-3) deficient]; the other two formulas had adequate
(C) 18:2(n-6) and 18:3(n-3), representing 8.3 and 0.8% energy,
respectively, [18:2(n-6)-18:3(n-3) adequate] (Table 1
). One of each of the 18:2(n-6) + 18:3(n-3) deficient and
18:2(n-6)+18:3(n-3) adequate formulas had 0.2% energy (0.4g/100 g
total fatty acids) 20:4(n-6) and 0.16% energy 22:6(n-3) (D+, C+,
respectively). The other two formulas had no other added oil
sources (D-, C-). The 20:4(n-6) and 22:6(n-3) were from
single-cell triglycerides and were included in the formula
during preparation by Nestlé Research Center (Laussanne,
Switzerland). The formulas contained 57.9 g fat and 4.143 MJ/L,
with a macronutrient and micronutrient composition similar to that used
previously (Innis and Dyer 1997
). Littermates were not
assigned to the same diet. The formula-fed piglets were
bottle-fed by hand to 18 d of age (Innis and Dyer 1997
). The procedures involving the piglets were approved by
the Animal Care Committee of the University of British Columbia and
conformed to the guidelines of the Canadian Council on Animal Care.
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The piglets were anesthetized (Ketaset® 37.5:3.75 mg/kg MTC
Pharmaceuticals, Cambridge, Canada; Bayvet Division, Chenango,
Etobicoke, Canada, respectively, by intramuscular injection) at 18 d of age, 3–4 h after the last feeding (Innis and Dyer 1997
). Blood samples were drawn by intracardiac puncture, and
the animals were killed by intracardiac injection of 200 mg
pentobarbital/kg. The brain was rapidly removed, weighed and the
frontal cortex dissected and frozen in liquid nitrogen. The remaining
cerebrum tissue was homogenized (5 mL/g, 0.32 mol sucrose/L, 15 mmol
Tris HCl/L with 1 mmol EDTA/L, 1 mmol MgCl/L and 1.5
mmol gluthatione/L, pH 7.4) then frozen in liquid nitrogen. All of the
samples were stored at -80°C until analysis.
Frontal cortex and total cerebrum lipid analyses.
Frontal cortex and total cerebrum lipids were extracted (Folch et al. 1957
), then phosphatidylcholine (PC),
phosphatidylethanolamine (PE), phosphatidylinositol (PI) and
phosphatidylserine (PS) were separated on thin layer chromatography
plates (Whatman PK6F Silica Gel 60 A) by using methyl
acetate/n-propanol/chloroform/methanol/KCl 0.25%
(25:25:28:10:7 v/v/v/v/v) followed by methyl
acetate/n-propanol/chloroform/methanol/KCl 0.25% (25:25:25:10:9
v/v/v/v/v) in the same dimension. The separated phospholipids were
recovered, the fatty acid components converted to their respective
methyl esters, separated, identified and quantified by gas liquid
chromatography (Innis et al. 1994a
). Total cerebrum
cholesterol was analyzed by using enzymatic reagents (Diagnostic
Chemical Limited, Charlottetown, Prince Edward Island, Canada), and
phospholipid was analyzed according to Chen et al.
(1956
).
Total cerebrum CNPase activity, DNA and protein.
The activity of brain 21, 31 cyclic nucleotide
31-phosphohydrolase (CNPase), which increases in parallel
with myelination (Norton and Cammer 1985
) was determined
according to Prohaska et al. (1973
). The brain DNA
concentration was estimated fluorometrically with DyNA Quant 200
(Hoefer, San Francisco, CA), with calf thymus DNA as the standard.
Protein was determined according to Lowry et al. (1951
).
Frontal cortex monoamines.
Frontal cortex (200 mg) was homogenized (Sonics Materials, Danbury, CT) in 760 µL of perchloric acid 0.1 mol/L, with 40 µL of 3,4-dihydroxybenzylamine (3 mg/L) as an internal standard. The resulting homogenate was then centrifuged at 172,400 xg, for 1 h at 4°C in a L7–55 ultracentrifuge equipped with 50.2 Ti type rotor (Beckman Instruments, Palo Alto, CA.). The supernatant was then transferred to a low volume insert vial (Waters Div. of Millipore, Milford, MA). The frontal cortex monoamine concentrations were then determined by HPLC, using a Waters Alliance 2690 separation module equipped with a refrigerated autosampler (Waters, Mississauga, Ontario, Canada) with electrochemical detection (EG&G Princeton Applied Res, Princeton, NJ, electrochemical detector model 400) with a glass carbon electrode cell block and reference electrode 3M NaCl/Sat AgCl filling solution. The analytical column was a Symmetry C18, 2.1 x 150 mm, coupled to a guard column Sentry Symmetry C18, 3.9 x 20 mm (Waters, Milford, MA). The mobile phase consisted of 6 g sodium acetate/L, 10 mg EDTA/L, 125 mg octyl sulfate sodium salt/L, 27 mL glacial acetic acid/L, and 20 mL HPLC grade methanol/L. The mobile phase was filtered and degassed by using a solvent filtration apparatus with GV 0.22 µm (pore size) Millipore filters. The separation was performed under isocratic conditions with a column temperature of 32°C and a flow rate of 0.3 mL/min, allowing for the separation of dopamine, serotonin, norepinephrine, and their major metabolites, 3,4-dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5-HIAA), as well as the precursors tyrosine and tryptophan. The working electrode potential was maintained at 775 mV and 5 nA for the range current.
Statistical analyses.
Results were compared between the groups by using two-way ANOVA, with the level of 18:2(n-6)-18:3(n-3) (D or C, respectively) and no addition or addition of 20:4(n-6) and 22:6(n-3) (- or +, respectively) as the main effects. The homogeneity of the variances was analyzed by the Levene test and was found to be not significantly different. Formal tests for significant difference were made by using Fisher's least significant difference and were performed only for ANOVA results with P < 0.05. The results given are means ± SEM, n = 6/group.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There were no significant differences in the brain weight among piglets fed the different diets (46.8 ± 0.5, 48.3 ± 1.3, 45.6 ± 1.4, 46.8 ± 1.5 g, for piglets in the D-, D+, C-, C + groups, respectively). Similarly, there were no significant differences in the brain protein, DNA, cholesterol or phospholipid concentrations, or CNPase activity among piglets fed the different formulas (data not shown).
The frontal cortex of the piglets fed the D- formula had a
significantly lower percentage of 18:2(n-6), 20:4(n-6), and 22:6(n-3)
and a higher percentage of 20:3(n-9) in PC; lower 18:2(n-6) and
20:4(n-6) and higher 20:3(n-9) in PE; lower 18:2(n-6) and 20:4(n-6) and
higher 20:3(n-9) in PI; and lower 18:2(n-6) and higher 20:3(n-9) in PS
than did piglets fed the C- formula (Fig. 1
). The effects of including 20:4(n-6) and 22:6(n-3) in the formula
depended on the formula content of the precursors 18:2(n-6) and
18:3(n-3) (P < 0.05). The frontal cortex of piglets
fed the D+ formula had a significantly higher percent 22:6(n-3) in PC,
PE, PI, and PS, and higher 20:4(n-6) in PC and PI, and lower 20:3(n-9)
in PC, PE, PI, and PS than in that of piglets fed the D- formula. In
contrast, the frontal cortex phospholipid fatty acid composition of
piglets fed the C+ formula was not different from that of piglets fed
the C- formula, except for a significantly higher percent of 22:6(n-3)
in PE and PI and higher 18:2(n-6) in PI and PS. The frontal cortex of
piglets fed the D+ formula had a significantly higher percentage of
22:6(n-3) in PE and PS and lower 18:2(n-6) in PS than that in piglets
fed the C+. The percentages of 20:3(n-9) in frontal cortex PC, PE, PI
and PS were not different between piglets fed the C- or C + diets.
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Piglets fed the formulas with 20:4(n-6) and 22:6(n-3) had significantly
higher frontal cortex dopamine, HVA and norepinephrine, as well as
tryptophan and serotonin concentrations than did piglets fed the
formulas without 20:4(n-6) and 22:6(n-3) (Fig. 2
). Piglets fed the D formulas deficient in 18:2(n-6)-18:3(n-3) had
significantly lower dopamine and serotonin concentrations than did
piglets fed the C formulas with adequate 18:2(n-6) and 18:3(n-3).
Piglets fed the D- formula had a significantly lower concentration of
dopamine and its degradation metabolites, DOPAC and HVA, and lower
serotonin and its degradation metabolite, 5-HIAA, in the frontal cortex
than did piglets fed the C- or C+ formula. Piglets fed the D+ formula
had significantly higher frontal cortex dopamine, norepinephrine,
DOPAC, HVA, serotonin and 5-HIAA concentrations than did piglets fed
the C- (P < 0.05). Thus, the concentrations of all
frontal cortex monoamines and metabolites in piglets fed D+ formula
were not different from those of piglets fed the C- or C+ adequate
formulas. The inclusion of 20:4(n-6) and 22:6(n-3) in the
18:2(n-6)-18:3(n-3) adequate formula had no significant effect on any
of the frontal cortex monoamines or metabolites measured (C+ compared
to C-).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Xu et al. 1996
). Alternatively, the
provision of a dietary 20:4(n-6) and 22:6(n-3) could spare the very
limited dietary supply of 18:2(n-6) and 18:3(n-3) for the brain.
The studies here cannot address the relative importance of plasma
18:2(n-6)-18:3(n-3) compared with 20:4(n-6) and 22:6(n-3) for brain
lipid synthesis under conditions of adequate 18:2(n-6)-18:3(n-3)
intake. However, piglets fed the formula with about 8.3% energy
18:2(n-6) and 0.8% energy 18:3(n-3) had levels of 20:4(n-6) in their
frontal cortex phospholipids that were not different from that of
piglets fed the same (adequate) formula or the deficient formula with
20:4(n-6) and 22:6(n-3). This finding is consistent with previous
studies that suggested that when provided with adequate 18:2(n-6) and
18:3(n-3), the newborn piglet is able to make sufficient 20:4(n-6) and
22:6(n-3), either in the liver or in the brain itself, to meet the
needs of the developing brain (Arbuckle et al. 1992
and 1994
). Others have shown the brain is able to form 20:4(n-6)
and 22:6(n-3) from the respective 18:2(n-6) and 18:3(n-3) precursors
(Clandinin et al. 1985
, Moore et al. 1990
and 1991
). The percentage of 22:6(n-3) was ~20 and 36% higher in
frontal cortex PE and PI in piglets fed the D+ and the D- formulas,
respectively, and ~9 and 24% higher in PE and PI of piglets fed the
C+ and C- formulas, respectively. Previous studies have shown that the
addition of 22:6(n-3) from fish oil to formula results in a
dose-dependant increase in brain and brain synaptic plasma membrane
PE 22:6(n-3), although to a much smaller extent than in the plasma or
liver (Arbuckle et al. 1991
and 1992
). Diets high in
22:6(n-3) were also shown to increase brain and retina22:6(n-3) in
rodents and nonhuman primates (Lin et al. 1990
,
Wainwright et al. 1997
, Weisinger et al. 1996
, Yeh et al. 1998
). This may suggest that
brain uptake and regulation of 20:4(n-6) and 22:6(n-3) differs;
however, dose-response studies of brain lipids after high intakes
of 20:4(n-6) do not seem to have been reported.
Behavioral changes in tests of learning and memory were noted in
several, but not all, studies with rodents fed diets very low in
18:2(n-6) and 18:3(n-3) or adequate in 18:2(n-6) but deficient in
18:3(n-3) (Bourre et al. 1989
, Enslen et al. 1991
, Frances et al. 1996
, Lamptey and Walker, 1976
, Wainwright and Ward, 1997
,
Yamamoto et al. 1988
). Whether or not changes in
neurotransmitter metabolism can explain the behavioral changes
associated with (n-6) and/or (n-3) fatty acid deficiency is not yet
clear. Studies with second generation rats fed a 18:3(n-3) deficient
diet reported lower frontal cortex dopamine, but not serotonin,
concentrations; reduced D2 receptor binding; and higher 5-HT2 receptor
density (Delion et al. 1994
and 1996
). Subsequent
studies with second generation rats fed a 18:3(n-3) deficient diet
found increased levels of dopamine metabolites, without modification of
basal dopamine levels, and reduced release of dopamine during
tyramine-stimulated, but not basal conditions, of microdialysis
(Zimmer et al. 1998
). Because dopamine stored in
synaptic vesicles is recruited to maintain requirements, and the lower
dopamine caused by the 18:3(n-3) deficiency was not accompanied by
changes in monoamine oxidase activity (Delion et al. 1994
), it was suggested that 18:3(n-3) deficiency decreases the
storage pool of dopamine (Zimmer et al. 1998
). Yoshida
et al. (1997
), on the other hand, based on evidence of
low synaptic vesicle densities after a learning task in rats fed a
(n-3) fatty acid deficient diet (safflower oil) compared to a high
(n-3) fatty acid diet (perilla oil), suggested changes in the turnover
rate of synaptic vesicles. Our studies with neonatal piglets showed
that feeding a formula similar in nutrient composition to milk (except
for fatty acids) and low in both 18:2(n-6) and 18:3(n-3) results in
lower frontal cortex concentrations of dopamine and in the
mitochondrial monoamine oxidase products DOPAC and HVA, as well as
serotonin and its product, 5-HIAA, after only 18 d feeding from
birth. The decrease in both dopamine and serotonin and in the
metabolites DOPAC, HVA and 5-HIAA in our studies with piglets suggests
the possibility of decreased synthesis, which will need to be evaluated
through measures of neurotransmitter synthesis and turnover. Possibly,
the effects of combined 18:2(n-6) and 18:3(n-3) deficiency are more
severe, or 20:4(n-6) may have specific or additional effects from (n-3)
fatty acids on frontal cortex dopamine and serotonin synthesis and
metabolism. It is also possible that the effects of (n-6) and (n-3)
fatty acids on brain function may differ between piglets and rats.
However, an important aspect of our studies with piglets is that the
dietary deficiency was imposed in the early neonatal period that is
associated with exclusive milk feeding by feeding formulas with a
defined fat composition. This avoids potential transfer of (n-6) and
(n-3) fatty acids from maternal stores via milk to the developing
young.
The explanation for the changes in frontal cortex dopamine and
serotonin, as well as the metabolites DOPAC, HVA and 5-HIAA, with
dietary (n-6) and (n-3) fatty acid deprivation is not known. The (n-6)
and/or (n-3) fatty acid composition of neural membranes could alter
membrane properties or the function of membrane associated transport
systems, receptors or enzymes, or possibly lead to structural changes
in developing synapses. In this regard several studies showed that
dietary (n-3) fatty acid deficiency results in reduced 22:6(n-3) in
synaptosomal membranes (Arbuckle and Innis 1992
, Bourre et al. 1989
, Foote et al. 1990
, Hrboticky et al. 1989
, Youyou et al. 1986
). Wainwright et al. (1999
) also
recently reported evidence of altered dendritic morphology in the
brains of 16-wk-old mice fed an EFA deficient diet through development.
The diet-induced changes in 20:4(n-6) and 22:6(n-3) in the frontal
cortex phospholipids of piglets fed the 18:2(n-6) and 18:3(n-3)
deficient diet in the studies presented here were relatively modest
when compared to the marked differences in frontal cortex monoaminergic
neurotransmitters. For example, the frontal cortex PI had 35.8 ± 0.7 and 40.1 ± 0.5% 20:4(n-6), and PE had 16.0 ± 0.3 and
21.2 ± 0.4% 22:6(n-3), whereas the frontal cortex concentration
of dopamine was 0.09 ± 0.0 umol/g and 1.04 ± 0.1 umol/g and
serotonin was 0.2 ± 0.0 umol/g and 1.81 ± 0.1 umol/g, for
piglets fed the D- and D+ formulas, respectively. Furthermore, the
effects of the formula fatty acid composition on frontal norepinephrine
were much smaller (4.09 ± 0.16, 4.97 ± 0.25 µg/g for
piglets fed the D- and D+ formulas, respectively) than for dopamine or
serotonin. Whether the effects of (n-6) and (n-3) fatty acids are
mediated by some mechanism other than a change in the membrane
phospholipid fatty acid composition, for example, involving specific
signaling systems, which may have developmental, neurotransmitter
and/or species specific relevance, and if neurotransmitters other than
those measured here are affected may be worth considering.
The 18:2(n-6)-18:3(n-3) deficient formula fed in our studies had a high content of 8:0–14:0, representing about 77% fatty acids, whereas 8:0–14:0 represented only about 20% fatty acids in the 18:2(n-6)-18:3(n-3) adequate formula. Thus, the possibility that the changes in frontal cortex monoamine metabolism were due to saturated rather than polyunsaturated fat needs to be considered. The addition of 20:4(n-6) and 22:6(n-3) to the 18:2(n-6)-18:3(n-3) deficient formula, however, increased dopamine, norepinephrine, serotonin, DOPAC, HVA and 5-HIAA in the frontal cortex. From this it is reasonable to believe that the changes in dopamine and serotonin were due to the absence of the (n-6) and (n-3) fatty acids, 20:4(n-6) and 22:6(n-3), and not to the high saturated fat content of the formula.
In summary, these studies showed that feeding an EFA deficient diet to the neonatal piglet for as little as 18 d from birth significantly decreased frontal cortex 20:4(n-6) and 22:6(n-3) and decreased the frontal cortex concentration of dopaminergic and serotoninergic neurotransmitters. The absence of decreased frontal cortex dopaminergic and serotoninergic neurotransmitters in piglets fed small amounts of 20:4(n-6) and 22:6(n-3), representing about 0.2% and 0.15% dietary energy, respectively, provide clear evidence of the role for 20:4(n-6) and/or 22:6(n-3) in normal brain function. The explanation for the effects of dietary (n-6) and (n-3) fatty acids on frontal cortex monoaminergic neurotransmitters, the relevance to early parenteral nutrition support without lipid, or to human diets containing oils very low in (n-6) and (n-3) fatty acids, is not yet known.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: C-, adequate without 20:4(n-6) and 22:6(n-3); C+, adequate without 20:4(n-6) and 22:6(n-3); D-, deficient
without 20:4(n-6) and 22:6 (n-3); D+, deficient with 20:4(n-6) and
22:6(n-3); DOPAC, 3,4-dihydroxyphenylacetic; EFA, essential fatty acid; HVA, homovanillic acid; PC, phosphatidylcholine; PE,
phosphatidylethanolamine; PI, phosphatidylinositol; PS, Phosphatidylserine; PUFA, polyunsaturated fatty acids.
Manuscript received March 3, 1999. Initial review completed April 28, 1999. Revision accepted July 5, 1999.
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