Whole body synthesis rates of DHA from alpha linolenic acid are greater than brain DHA accretion and uptake rates in adult rats
Whole body synthesis rates of DHA from alpha linolenic acid are greater than brain DHA accretion and uptake rates in adult rats
Year: 2014
Authors: Domenichiello, A.F. Chen, C.T. Trepanier, M-O. Stavro, P.M. Bazinet, R.P.
Publication Name: J Lipid Res
Publication Details: Volume 55; Issue 1; Pages 62-74
Abstract:
Docosahexaenoic acid (DHA) is important for brain function, however, the exact amount required for the brain is not agreed upon. While it is believed that the synthesis rate of DHA from linolenic acid (ALA) is low, how this synthesis rate compares with the amount of DHA required to maintain brain DHA levels is unknown. The objective of this work was to assess whether DHA synthesis from ALA is sufficient for the brain. To test this, rats consumed a diet low in n 3 PUFAs, or a diet containing ALA or DHA for 15 weeks. Over the 15 weeks, whole body and brain DHA accretion was measured, while at the end of the study, whole body DHA synthesis rates, brain gene expression, and DHA uptake rates were measured. Despite large differences in body DHA accretion, there was no difference in brain DHA accretion between rats fed ALA and DHA. In rats fed ALA, DHA synthesis and accretion was 100 fold higher than brain DHA accretion of rats fed DHA. Also, ALA fed rats synthesized approximately 3 fold more DHA than the DHA uptake rate into the brain. This work indicates that DHA synthesis from ALA may be sufficient to supply the brain. (Authors abstract)
Whole body synthesis rates of DHA from alpha linolenic acid are greater than brain DHA accretion and uptake rates in adult rats. Linolenic acid (ALA) is the most accessible and sustainable source of omega 3 polyunsaturated fatty acids in the global diet. ALA is also a precursor to docosahexaenoic acid (DHA), an n 3 PUFA that is particularly enriched within the brain. While it is generally accepted that DHA is important for normal brain function, the amount of DHA required by the brain is not agreed upon. N 3 PUFAs cannot be synthesized by mammals de novo, therefore, DHA must be consumed from dietary sources or be synthesized from shorter chain n 3 PUFAs. To date, reports suggest that the synthesis rate of DHA from ALA is low and perhaps even below detection. However, plasma concentrations of DHA in vegans are only 0 to 40 per cent lower than fish eaters despite having no dietary DHA. Furthermore, vegan and vegetarian populations do not have an increased risk of neurological disorders. The lack of concordance between the low DHA synthesis rates and the relatively normal plasma DHA concentrations in vegans may be due to the methods used to measure DHA synthesis. In humans, an ALA tracer is administered orally and the appearance of labeled DHA in the plasma is measured for up to 2 weeks. From the area under the curve (AUC) of labeled DHA appearance, the fractional conversion of DHA is calculated. Alternatively, plasma labeled DHA concentrations over time can be used in modeling programs to determine fractional conversion. In both cases, the calculations may preclude a quantitative measurement of the DHA synthesis rate and allow only a comparison between study groups. Another concern is the finding that up to 57 per cent of the tracer remains in the adipose after oral consumption of labeled ALA. Because the human adipose half life can be longer than one year, it is possible that the tracer is unavailable for DHA synthesis during the study period. In this study, it was shown that rats fed ALA and DHA accreted similar amounts of brain DHA, which together with kinetic findings suggest DHA synthesis from ALA is likely sufficient to maintain brain DHA levels. The investigators also mimicked, in rats, the methods used in humans to determine DHA synthesis from ALA by subjecting rats to a gavage with labeled ALA. It was shown that the rates from this experiment, in rats, were comparable to the results of previously published human studies. Collectively, these results indicate that the rat is an appropriate model for measuring brain DHA synthesis and that brain DHA can be supplied from dietary ALA. Brain DHA levels in the adult rat can be maintained by dietary ALA just as well as by dietary DHA. This was supported by the finding that dietary ALA and DHA resulted in the same level and accretion of brain DHA after 15 weeks. From the 15 week balance study, the accretion of brain DHA in the ALA and DHA fed rats did not significantly differ, and equaled 0.032 plus 0.005 mol per day and 0.042 plus 0.007 mol per day, respectively. Previous work in this lab found that mice fed DHA at a concentration of 2 per cent of the fatty acids attained maximal DHA concentrations in the brain. Because rats fed the ALA diet were able to synthesize 100 fold more DHA than the amount of DHA accreted in the brains of rats consuming the DHA diet, and there were no significant differences in brain DHA concentrations or accretions in rats fed these two diets, it is likely that rats fed the ALA diet were able to synthesize sufficient DHA to maintain brain DHA levels. It is generally accepted that the rat can synthesize more DHA than the human; however, the methods used to measure DHA synthesis in the human have not been validated in the rat. This study showed that despite large differences in fatty acid accumulation in the body, rats fed a diet containing DHA or ALA making up 2 per cent of the fatty acids did not have differences in brain DHA accumulation. Using in vivo kinetic approaches, we were able to determine that animals consuming the ALA diet synthesized DHA at rates that exceed the rate of DHA uptake from the plasma into the brain. Importantly, rats consuming the ALA diet had a lower uptake rate of DHA into the brain than rats consuming DHA. As the uptake rate of DHA into the brain has been shown to match rates of brain DHA metabolism, it is likely that decreased brain DHA metabolism, in combination with an increased rate of DHA synthesis from ALA, is the reason that brain DHA accretion in rats fed the ALA diet did not differ from the rats fed the DHA diet. The overall results from this study indicate that DHA synthesis from ALA in the rat may be sufficient to maintain brain DHA concentrations in the absence of dietary DHA consumption. Importantly, the steady state infusion method can be used in humans to calculate an actual DHA synthesis rate that can be compared with brain DHA uptake rates measured in humans with positron emission tomography scanning. (Editors comments)
Whole body synthesis rates of DHA from alpha linolenic acid are greater than brain DHA accretion and uptake rates in adult rats. Linolenic acid (ALA) is the most accessible and sustainable source of omega 3 polyunsaturated fatty acids in the global diet. ALA is also a precursor to docosahexaenoic acid (DHA), an n 3 PUFA that is particularly enriched within the brain. While it is generally accepted that DHA is important for normal brain function, the amount of DHA required by the brain is not agreed upon. N 3 PUFAs cannot be synthesized by mammals de novo, therefore, DHA must be consumed from dietary sources or be synthesized from shorter chain n 3 PUFAs. To date, reports suggest that the synthesis rate of DHA from ALA is low and perhaps even below detection. However, plasma concentrations of DHA in vegans are only 0 to 40 per cent lower than fish eaters despite having no dietary DHA. Furthermore, vegan and vegetarian populations do not have an increased risk of neurological disorders. The lack of concordance between the low DHA synthesis rates and the relatively normal plasma DHA concentrations in vegans may be due to the methods used to measure DHA synthesis. In humans, an ALA tracer is administered orally and the appearance of labeled DHA in the plasma is measured for up to 2 weeks. From the area under the curve (AUC) of labeled DHA appearance, the fractional conversion of DHA is calculated. Alternatively, plasma labeled DHA concentrations over time can be used in modeling programs to determine fractional conversion. In both cases, the calculations may preclude a quantitative measurement of the DHA synthesis rate and allow only a comparison between study groups. Another concern is the finding that up to 57 per cent of the tracer remains in the adipose after oral consumption of labeled ALA. Because the human adipose half life can be longer than one year, it is possible that the tracer is unavailable for DHA synthesis during the study period. In this study, it was shown that rats fed ALA and DHA accreted similar amounts of brain DHA, which together with kinetic findings suggest DHA synthesis from ALA is likely sufficient to maintain brain DHA levels. The investigators also mimicked, in rats, the methods used in humans to determine DHA synthesis from ALA by subjecting rats to a gavage with labeled ALA. It was shown that the rates from this experiment, in rats, were comparable to the results of previously published human studies. Collectively, these results indicate that the rat is an appropriate model for measuring brain DHA synthesis and that brain DHA can be supplied from dietary ALA. Brain DHA levels in the adult rat can be maintained by dietary ALA just as well as by dietary DHA. This was supported by the finding that dietary ALA and DHA resulted in the same level and accretion of brain DHA after 15 weeks. From the 15 week balance study, the accretion of brain DHA in the ALA and DHA fed rats did not significantly differ, and equaled 0.032 plus 0.005 mol per day and 0.042 plus 0.007 mol per day, respectively. Previous work in this lab found that mice fed DHA at a concentration of 2 per cent of the fatty acids attained maximal DHA concentrations in the brain. Because rats fed the ALA diet were able to synthesize 100 fold more DHA than the amount of DHA accreted in the brains of rats consuming the DHA diet, and there were no significant differences in brain DHA concentrations or accretions in rats fed these two diets, it is likely that rats fed the ALA diet were able to synthesize sufficient DHA to maintain brain DHA levels. It is generally accepted that the rat can synthesize more DHA than the human; however, the methods used to measure DHA synthesis in the human have not been validated in the rat. This study showed that despite large differences in fatty acid accumulation in the body, rats fed a diet containing DHA or ALA making up 2 per cent of the fatty acids did not have differences in brain DHA accumulation. Using in vivo kinetic approaches, we were able to determine that animals consuming the ALA diet synthesized DHA at rates that exceed the rate of DHA uptake from the plasma into the brain. Importantly, rats consuming the ALA diet had a lower uptake rate of DHA into the brain than rats consuming DHA. As the uptake rate of DHA into the brain has been shown to match rates of brain DHA metabolism, it is likely that decreased brain DHA metabolism, in combination with an increased rate of DHA synthesis from ALA, is the reason that brain DHA accretion in rats fed the ALA diet did not differ from the rats fed the DHA diet. The overall results from this study indicate that DHA synthesis from ALA in the rat may be sufficient to maintain brain DHA concentrations in the absence of dietary DHA consumption. Importantly, the steady state infusion method can be used in humans to calculate an actual DHA synthesis rate that can be compared with brain DHA uptake rates measured in humans with positron emission tomography scanning. (Editors comments)
